Use of tapinarof for the treatment of atopic dermatitis

ABSTRACT

Topical compositions and methods for using topical compositions comprising tapinarof to treat mild to moderate atopic dermatitis or plaque psoriasis are described herein. Also described are clinical endpoints for treatment of subjects diagnosed with mild to moderate atopic dermatitis, wherein about 5% to about 35% of body surface area was affected, and Investigator Global Assessment (IGA) score was greater than or equal to 3. Also described are clinical endpoints for treatment of subjects diagnosed with chronic mild to moderate plaque psoriasis for greater than or equal to 6 months, wherein about 3% to about 20% of body surface area was affected, and Physician Global Assessment (PGA) score was greater than or equal to 2.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.18/163,631 filed Feb. 2, 2023, which is a continuation of U.S. patentapplication Ser. No. 17/871,663 filed Jul. 22, 2022, now U.S. Pat. No.11,590,088 issued Feb. 28, 2023, which is a continuation of U.S. patentapplication Ser. No. 16/682,485 filed Nov. 13, 2019, now U.S. Pat. No.11,497,718 issued Nov. 15, 2022, which claims the benefit of U.S.Provisional Application No. 62/760,704 filed Nov. 13, 2018 and U.S.Provisional Application No. 62/833,276 filed Apr. 12, 2019, and U.S.patent application Ser. No. 16/682,485 is a continuation-in-part of U.S.patent application Ser. No. 16/682,476 filed Nov. 13, 2019, abandoned,which claims the benefit of U.S. Provisional Application No. 62/760,692filed Nov. 13, 2018 and U.S. Provisional Application No. 62/833,269filed Apr. 12, 2019, each of which are hereby incorporated by referencein their entirety.

SUMMARY

Embodiments of the invention are directed to methods for treating atopicdermatitis in a subject comprising topically administering once a day tothe subject in need thereof a topical composition containing about 0.5%to about 1.0% tapinarof, wherein one or more symptom of psoriasis isimproved. In some embodiments, the atopic dermatitis is mild tomoderate.

Embodiments of the invention are directed to methods for treatingchronic plaque psoriasis in a subject comprising topically administeringonce a day to the subject in need thereof a topical compositioncontaining about 0.5% to about 1.0% tapinarof, wherein one or moresymptom of psoriasis is improved. In some embodiments, the chronicplaque psoriasis is mild to moderate.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and advantages of the presentinvention, reference should be made to the following detaileddescription taken in connection with the accompanying drawings, inwhich:

FIG. 1 demonstrates the proportion of patients who achieved an IGA scoreof clear or almost clear (0 or 1) and a minimum 2-grade improvement frombaseline to each study visit using non-responder imputation.

FIG. 2 shows the clinical feature of two patients with atopic dermatitiswho received tapinarof (1% QD).

FIG. 3 demonstrates that the Tapinarof 10% QD concentration demonstratedstatistical significance (*) over the vehicle at α=0.05 level after twoweeks of treatment.

FIG. 4 demonstrates that a difference can be seen after 2 weeks in thetapinarof groups compared to the vehicle groups.

FIG. 5 a presents subject impression of change in severity of ADsymptoms at Week 12.

FIG. 5 b presents subject impression of change in severity of pruritussymptoms at Week 12.

FIG. 6 depicts the proportion of patients who achieved a PGA score of 0or 1 and a minimum 2-grade improvement from baseline (mITT Population)(OC). All tapinarof groups showed a clear separation from vehiclereaching statistical significance after 8 weeks of treatment, with 1%concentration showing highest response rates.

FIG. 7 depicts subject impression of change in severity of psoriasissymptoms at Week 12.

FIG. 8 depicts subject impression of change in severity of pruritussymptoms at Week 12.

FIG. 9 depicts the proportion of patients with greater than or equal to75% improvement in PASI from Baseline (mITT Population) (OC).

FIG. 10 shows the proportion of subjects with ≥75% improvement inPsoriasis Area and Severity Index from baseline to week 12 and week 16(end of treatment follow-up). Difference versus vehicle is statisticallysignificant at *P<0.05, **P<0.01, ***P<0.001. n designates the number ofsubjects with results available at week 12. BID, twice daily; QD, oncedaily.

FIG. 11 shows the proportion of subjects with ≥90% improvement inpsoriasis area and severity index from baseline to Week 12 and Week 16(end of treatment follow-up). Difference versus vehicle is statisticallysignificant at *P<0.05, **P<0.01. n is number of subjects with availableresults at Week 12. BID, twice daily; QD, once daily.

FIG. 12 depicts the mean change in total target lesion grading scorestfrom baseline to Week 12 and Week 16 (end of treatment follow-up).Difference versus vehicle is statistically significant at **P<0.01,***P<0.001. n is number of subjects with available results at Week 12.†Erythema, scaling, and induration of plaque thickness. BID, twicedaily; QD, once daily.

FIG. 13 shows plaque psoriasis at baseline (left panel), Week 8(middle), and Week 12 (right panel). Representative photographs of onetarget lesion in one subject (randomized to receive tapinarof 1% QD)with baseline plaque psoriasis, plus responses at Week 8 and Week 12.QD, once daily.

FIG. 14 depicts subject impression of change in severity of psoriasissymptoms at Week 12. n is number of subjects with available results atWeek 12. BID, twice daily; QD, once daily.

FIG. 15 depicts subject impression of change in severity of pruritussymptoms at Week 12. n is number of subjects with available results atWeek 12. BID, twice daily; QD, once daily.

FIG. 16 depicts the mean change from baseline in 9 items of thepsoriasis symptom diary at Week 12. Difference versus vehicle isstatistically significant at *P<0.05, **P<0.01, ***P<0.001. n designatesthe number of subjects with results available at Week 12. BID, twicedaily; PSD, Psoriasis Symptom Diary; QD, once daily.

FIG. 17 depicts investigator-assessed tolerability scores over time.Investigator-assessed irritation scores (0-4) assess the presence andoverall degree of irritation at the application sites. A score of 3 or 4was reported to be an adverse event; study treatment was discontinued ifa score of 4 was noted. n designates the number of subjects withavailable results at Week 12 and is the denominator in calculating thepercentage at Week 12. BID, twice daily; QD, once daily.

FIG. 18 depicts subject-reported tolerability scores over time.Subject-reported tolerability scores (0-4) assess the presence anddegree of burning/stinging and itching at the application sites withinapproximately 2 hours following application of the study treatment. Thescore will ideally represent an ‘average’ across all application sites.n designates the number of subjects with results available at Week 12and is the denominator in calculating the percentage at Week 12. BID,twice daily; QD, once daily.

FIG. 19 shows the study design.

FIG. 20 depicts the proportion of Subjects who achieved PGA response atWeek 12 by % BSA Affected at Baseline.

FIG. 21 depicts the proportion of Subjects who achieved PGA response atWeek 12 by Duration of Psoriasis at Baseline.

FIG. 22 depicts the proportion of Subjects who achieved PGA response atWeek 12 by Fitzpatrick Skin Type.

DETAILED DESCRIPTION

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey its scope to those skilled in theart.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 mg to 8μmg is stated, it is intended that 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7mg are also explicitly disclosed, as well as the range of values greaterthan or equal to 1 mg and the range of values less than or equal to 8mg.

All percentages, parts and ratios are based upon the total weight of thetopical compositions and all measurements made are at about 25° C.,unless otherwise specified.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference toa “subject” includes a single subject as well as two or more subjects;reference to an “excipient” includes a single excipient as well as twoor more of the same or different excipients, and the like.

The word “about” when immediately preceding a numerical value means arange of plus or minus 10% of that value, e.g., “about 50” means 45 to55, “about 25,000” means 22,500 to 27,500, etc., unless the context ofthe disclosure indicates otherwise, or is inconsistent with such aninterpretation. For example, in a list of numerical values such as“about 49, about 50, about 55, “about 50” means a range extending toless than half the interval(s) between the preceding and subsequentvalues, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases“less than about” a value or “greater than about” a value should beunderstood in view of the definition of the term “about” providedherein.

The terms “administer,” “administering” or “administration” as usedherein refer to either directly administering a compound (also referredto as an agent of interest) or pharmaceutically acceptable salt of thecompound (agent of interest) or a topical composition to a subject.

The term “carrier” as used herein encompasses carriers, excipients, anddiluents, meaning a material, composition or vehicle, such as a liquidor solid filler, diluent, excipient, solvent or encapsulating materialinvolved in carrying or transporting a pharmaceutical, cosmetic or otheragent across a tissue layer such as the stratum corneum or stratumspinosum.

The transitional term “comprising,” which is synonymous with“including,” “containing,” or “characterized by,” is inclusive oropen-ended and does not exclude additional, unrecited elements or methodsteps. By contrast, the transitional phrase “consisting of” excludes anyelement, step, or ingredient not specified in the claim. Thetransitional phrase “consisting essentially of” limits the scope of aclaim to the specified materials or steps “and those that do notmaterially affect the basic and novel characteristic(s)” of the claimedinvention. In embodiments or claims where the term comprising is used asthe transition phrase, such embodiments can also be envisioned withreplacement of the term “comprising” with the terms “consisting of” or“consisting essentially of.”

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The terms “effective amount” and “therapeutically effective amount” areused interchangeably in this disclosure and refer to an amount of acompound that, when administered to a subject, is capable of reducing asymptom of a disorder in a subject or enhance the texture, appearance,color, sensation, or hydration of the intended tissue treatment area.The actual amount which comprises the “effective amount” or“therapeutically effective amount” will vary depending on a number ofconditions including, but not limited to, the severity of the disorder,the size and health of the patient, and the route of administration. Askilled medical practitioner can readily determine the appropriateamount using methods known in the medical arts.

The phrase “pharmaceutically acceptable” or “cosmetically acceptable” isemployed herein to refer to those agents of interest/compounds, salts,compositions, dosage forms, etc., which are—within the scope of soundmedical judgment—suitable for use in contact with the tissues of humanbeings and/or other mammals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio. In some aspects, pharmaceuticallyacceptable means approved by a regulatory agency of the federal or astate government, or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in mammals (e.g., animals), and moreparticularly, in humans.

The term “salts” as used herein embraces pharmaceutically acceptablesalts commonly used to form alkali metal salts of free acids and to formaddition salts of free bases. The nature of the salt is not critical,provided that it is pharmaceutically acceptable. The term “salts” alsoincludes solvates of addition salts, such as hydrates, as well aspolymorphs of addition salts. Suitable pharmaceutically acceptable acidaddition salts can be prepared from an inorganic acid or from an organicacid. Non-limiting examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoricacid. Appropriate organic acids can be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containingcarboxylic acids and sulfonic acids, for example formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric andgalacturonic acid.

The term “patient” and “subject” are interchangeable and may be taken tomean any human which may be treated with compounds of the presentinvention. In some embodiments, the patient or subject is an adult,adolescent, child or infant. In some embodiments, the patient or subjectis an adolescent (i.e., 12-17 years old). In some embodiments, thepatient or subject is younger than 2 years old. In some embodiments, thepatient or subject is 18 years old or older. In some embodiments, thepatient or subject is between the age of 18 and 75.

The term “treating” is used herein, for instance, in reference tomethods of treating a skin disorder or a systemic condition, andgenerally includes the administration of a compound or composition whichreduces the frequency of, or delays the onset of, symptoms of a medicalcondition or enhance the texture, appearance, color, sensation, orhydration of the intended tissue treatment area of the tissue surface ina subject relative to a subject not receiving the compound orcomposition. This can include reversing, reducing, or arresting thesymptoms, clinical signs, and underlying pathology of a condition in amanner to improve or stabilize a subject's condition.

By hereby reserving the right to proviso out or exclude any individualmembers of any such group, including any sub-ranges or combinations ofsub-ranges within the group, that can be claimed according to a range orin any similar manner, less than the full measure of this disclosure canbe claimed for any reason. Further, by hereby reserving the right toproviso out or exclude any individual substituents, analogs, compounds,ligands, structures, or groups thereof, or any members of a claimedgroup, less than the full measure of this disclosure can be claimed forany reason. Throughout this disclosure, various patents, patentapplications and publications are referenced. The disclosures of thesepatents, patent applications and publications in their entireties areincorporated into this disclosure by reference in order to more fullydescribe the state of the art as known to those skilled therein as ofthe date of this disclosure. This disclosure will govern in the instancethat there is any inconsistency between the patents, patent applicationsand publications cited and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

Atopic dermatitis (AD) (also called atopic eczema) is an intenselypruritic, chronic, relapsing, inflammatory skin disease. Thecharacteristic signs and symptoms of AD include sensations of pruritusand burning, xerosis, erythematous papules and plaques, exudation,crusting, and lichenification. Quality of life is affected through sleepdeprivation due to the intense and constant itching, as well as thestigma associated with having a visible skin disease. Up to 30% ofchildren may be affected by AD at some point, and 1% to 3% of adultshave AD. Currently there is no curative therapy. Stabilizing the diseaseand reducing the number and severity of flares are the primary goals oftreatment. Topical treatments directed at skin inflammation are a keyfactor in disease management, as is symptomatic relief of itching.Although multiple topical treatment options are available, there stillremains a need for a topical treatment that combines a high level ofefficacy with an acceptable safety profile that permits application to alarge body surface area (BSA) without restrictions on duration oftreatment.

The cause of AD is multifactoral, with genetic and environmentalfactors, deficient skin barrier function, and impaired immune response.The inflammatory component is thought to be mediated primarily by theTh2 type T-cell activation pathway, although in chronic AD skin lesions,a shift towards a Th1-driven pathway has been described. Tapinarofinhibits the secretion of multiple pro-inflammatory cytokines andchemokines (e.g., Th2 cytokines and leukotriene B4), inhibits moleculesinvolved in the adhesion and recruitment of cells involved in thepathogenesis of AD, and activates the aryl hydrocarbon receptor (AhR)and nuclear factor-erythroid 2-related factor-2 (Nrf2) anti-inflammatorypathways.

Psoriasis is a common, chronic relapsing inflammatory skin disease withrecurrent episodes of prominently erythematous and scaly patches(plaques). Approximately 2 to 3% of the global population is affected bypsoriasis; those affected are predominantly adults, who are most oftendiagnosed between the ages of 18 to 35 years. Psoriasis disrupts dailyactivities such as work and/or school attendance, interpersonalrelationships, recreational activities, and intimacy, therebysignificantly impacting sufferers' quality of life. Furthermore,psoriasis sufferers can also have co-morbidities such as arthritis,depression, inflammatory bowel disease, and cardiovascular (CV)diseases.

Up to 80% of patients have mild to moderate plaque-type psoriasis, whichis generally managed with topical treatments. Topically-appliedcorticosteroids and Vitamin D analogs, alone or in combination, are themost commonly used products in the treatment of psoriasis. Vitamin Danalogs are moderately efficacious as monotherapy, while application oftopical corticosteroids—particularly the very potent ones—is restrictedin terms of body areas that can be treated and the duration of use dueto the well-known application site and systemic adverse drug reactions.

Although numerous topical treatment options are available, there stillremains a need for a topical treatment that combines a high level ofefficacy with an acceptable safety profile that permits application to alarge body surface area (BSA) without restrictions on duration oftreatment.

Tapinarof is a fully synthetic hydroxylated stilbene and new molecularentity that is a novel anti-inflammatory agent for the topical treatmentof AD and plaque psoriasis.

Psoriatic skin lesions contain elevated numbers of activated T-cells,which have a key role in the pathogenesis of inflammatory diseasesthrough the proliferation and secretion of pro-inflammatory cytokines.The drug likely mediates its effects via the aryl hydrocarbon receptor(AhR) agonist and nuclear factor erythroid 2-related factor 2 (Nrf2)because the pattern of pro-inflammatory mediators inhibited by tapinarofis different from that of corticosteroids, calcineurin inhibitors,vitamin D analogs, and other immunosuppressive agents commonly used totreat AD and psoriasis. Rather, the profile of biological responseselicited by tapinarof most closely matches that of the dual activationproperties of coal tar, a common nonprescription treatment forpsoriasis. Together, existing data identify tapinarof as a non-steroid,therapeutic AhR-modulating agent (TAMA), which is a unique mechanism ofaction compared with existing therapies.

Clinical studies of Tapinarof cream with up to 12 weeks of treatmentwere conducted using a different formulation. These studies suggestedevidence of efficacy in treatment of AD and psoriasis, and also providea preliminary understanding of potential adverse events (AEs) and theoverall safety profile of the active compound.

It was surprisingly and unexpectedly found that the 1% tapinarof creamformulation applied topically once daily was just as effective as the 1%twice daily. This is surprising because both the 0.5% and 1%concentrations demonstrated an acceptable safety profile when appliedonce or twice daily but the 1% concentration was shown to be moreeffective than the 0.5% concentration, accordingly, one would haveexpected that a twice daily application would have been even moreeffective than a once daily application. A faster onset of action wasobserved with 1% dosing groups compared with the 0.5% dosing groups;fast onset of action is an important consideration for topicalmedications. A once daily application regimen may reduce systemicexposure as the atopic dermatitis is treated, thereby providing a betterefficacy and safety profile for a drug intended for long-term use totreat a chronic condition. In addition, once daily application mayimprove treatment adherence compared to more frequent dosingadministrations.

Compositions

Embodiments of the invention are directed to topical compositionscomprising 3,5-Dihydroxy-4-isopropyl-trans-stilbene or apharmaceutically acceptable salt thereof. Throughout this disclosure3,5-Dihydroxy-4-isopropyl-trans-stilbene is referred to as tapinarof,and is also known as (E)-2-isopropyl-5-styrylbenzene-1,3 diol, with theempirical formula C₁₇H₁₈O₂, a molecular weight of 254.32, and thefollowing structure:

In embodiments, the topical composition is an emulsion. In embodiments,the topical composition is an oil-in-water emulsion. In an embodiment,the topical composition of tapinarof or a pharmaceutically acceptablesalt thereof, comprises an oil phase, and a water phase, creating anemulsion, and wherein the emulsion composition is homogenous. In anembodiment, tapinarof, or pharmaceutically acceptable salt thereof issolubilized in the oil phase of the emulsion composition. Inembodiments, the oil phase is comprised of medium chain triglycerides,propylene glycol, non-ionic emulsifying wax, diethylene glycol monoethylether, polyoxyl stearyl ether-2, polysorbate 80, polyoxyl stearylether-20, benzoic acid, and butylated hydroxytoluene. In embodiments,the water phase is comprised of sodium citrate, edetate disodium, citricacid monohydrate, and water.

In certain embodiments described herein, the topical compositioncomprises about 0.50% to about 1.0% tapinarof, or a pharmaceuticallyacceptable salt thereof. In certain embodiments described herein, thetopical composition comprises about 0.50% tapinarof, or apharmaceutically acceptable salt thereof. In certain embodimentsdescribed herein, the topical composition comprises about 1.0%tapinarof, or a pharmaceutically acceptable salt thereof.

In certain embodiments described herein, the topical compositioncomprises about 50.00% to about 75.00% water, about 0.05% to about 0.50%sodium citrate, about 0.01% to about 2.00% citric acid, about 0.01% toabout 1.00% disodium EDTA, about 5.00% to about 25.00% propylene glycol,about 0.10% to about 5.00% diethylene glycol monoethyl ether, about0.01% to about 1.00% butylated hydroxytoluene, about 0.01% to about1.00% benzoic acid, about 5.00% to about 10.00% emulsifying wax, about5.00% to about 25.00% medium chain triglycerides (MCT), about 0.50% toabout 5.00% polysorbate 80, about 0.50% to about 5.00% steareth 2, andabout 0.50% to about 5.00% steareth 20.

In certain embodiments, the topical composition comprises 0.50%tapinarof, or a pharmaceutically acceptable salt thereof, 65.18% water,0.19% sodium citrate, 0.08% citric acid, 0.10% disodium EDTA, 10.00%propylene glycol, 2.00% diethylene glycol monoethyl ether, 0.10%butylated hydroxytoluene, 0.25% benzoic acid, 7.20% emulsifying wax,10.00% medium chain triglycerides (MCT), 1.50% polysorbate 80, 1.80%steareth 2, and 1.10% steareth 20.

In certain embodiments, the topical composition comprises 1.00%tapinarof, or a pharmaceutically acceptable salt thereof, 64.68% water,0.19% sodium citrate, 0.08% citric acid, 0.10% disodium EDTA, 10.00%propylene glycol, 2.00% diethylene glycol monoethyl ether, 0.10%butylated hydroxytoluene, 0.25% benzoic acid, 7.20% emulsifying wax,10.00% medium chain triglycerides (MCT), 1.50% polysorbate 80, 1.80%steareth 2, and 1.10% steareth 20. In another embodiment, theemulsifying wax is a proprietary blend known as “Polawax NF” (RegisteredTrademark) (Croda Inc, Edison, N.J., USA).

In embodiments, the topical composition may include pharmaceutically orcosmetically acceptable excipients, additives or other active agents asdescribed herein.

In embodiments, the topical compositions may further include one or morepharmaceutical and/or cosmetically acceptable excipients selected fromthe group consisting of diluents, fillers, disintegrants, binders,lubricants, surfactants, hydrophobic vehicles, water soluble vehicles,emulsifiers, buffers, humectants, moisturizers, solubilizers,preservatives, colorants, plastizers, carriers, excipients, orcombinations thereof. The person of ordinary skill in the art can referto various pharmacologic references such as, for example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979) and Goodman &Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co, New York (1980) for guidance in determining theamount of such components in the topical compositions and formulationsof embodiments.

In embodiments, the topical compositions may include emollient orlubricating vehicles that help hydrate the skin can also be used.Examples of suitable bases or vehicles for preparing hydratingcompositions for use with a subject skin are petrolatum, petrolatum plusvolatile silicones, lanolin, cold cream (USP), and hydrophilic ointment(USP).

In embodiments, the topical compositions may include a second activeagent. In embodiments, the second active agent is selected fromdupilumab; crisaborole; calcineurin inhibitors, such as tacrolimus andpimecrolimus; antibiotics; hydrocortisone; corticosteriods, such asprednisone; antihistamines, such as cetirizine, fexofenadine,diphenhydramine; and combinations thereof. In embodiments, the secondactive agent is selected from apremilast (Otezla™); adalimumab;secukinumab; guselkumab; ixekizumab; etanercept; infliximab;ustekinumab; golimumab; apremilast; topical corticosteriods (TCS), suchas prednisone; vitamin D; vitamin D derivatives, such as calcipotrieneor calcitriol; combination of calcipotriene and betamethasonedipropionate (Enstilar™) anthralin; methotrexate; cyclosporine; vitaminA; vitamin A derivatives, such as retinoids, tazarotene, or acitretin;calcineurin inhibitors, such as tacrolimus and pimecrolimus;thioguanine; hydroxyurea; salicylic acid; coal tar; and combinationsthereof.

In embodiments, the topical compositions may be formulated in anyformulation suitable for topical administration, including, but notlimited to, a solution, fluid, emulsion, suspension, solid, semi-solid,jelly, paste, gel, hydrogel, ointment, lotion, emulsion, cream, foam,mousse, liquid, spray, suspension, dispersion, powder, aerosol, ortransdermal patch. Formulations described in U.S. Patent PublicationNos. 2016/0338973, 2018/0064656, and 2019/0144367 are incorporatedherein by reference in their entirety.

In embodiments, the topical compositions described herein may beformulated as a liquid. Liquid dosage forms for topical administrationmay include diluents such as, for example, alcohols, glycols, oils,water, and the like. Such topical compositions may also include wettingagents or emulsifiers. In some embodiments, the topical compositions ofembodiments may be formulated as oil-in-water or water-in-oil emulsion.A cream can be a water-in-oil (w/o) emulsion in which an aqueous phaseis dispersed in an oil phase, or an oil-in-water (o/w) emulsion in whichan oil is dispersed within an aqueous base. An ointment generally refersto a more viscous oil-in-water cream. Traditional ointment bases (i.e.,carrier) include hydrocarbons (petrolatum, beeswax, etc.) vegetableoils, fatty alcohols (cholesterol, lanoilin, wool alcohol, stearylalcohol, etc.) or silicones. Insoluble solids such as starch, zincoxide, calcium carbonate, or talc can also be used in ointments andcreams. Gel forms of the topical compositions described above can beformed by the entrapment of large amounts of aqueous oraqueous-alcoholic liquids in a network of polymers or of colloidal solidparticles. Such polymers or colloids (gelling or thickening agents) aretypically present at concentrations of less than 10% w/w and includecarboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, methyl cellulose, sodium alginate, alginic acid, pectin,tragacanth, carrageen, agar, clays, aluminum silicate, carbomers, andthe like.

In embodiments, the topical compositions described herein may beformulated as aerosols, in which the topical composition is dissolved ina propellant such as dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas, and aco-solvent such ethanol, acetone, hexadecyl alcohol, and the like andcombinations thereof.

In embodiments, the topical compositions can be in the form ofhydrogels. Hydrogels are typically prepared by cross-linking variousmonomers and/or polymers to provide a three-dimensional polymer network.Non-limiting examples of polymers include, polyoxyethylene-polypropyleneblock copolymers, ionic poly saccharides, such as chitosan or sodiumalginate, cellulose, and biodegradable polymers, such as poly-lactides(PLA) and poly-glycolides (PGA), butylene succinate (PBS),polyhydroxyalkanoate (PHA), poly caprolactone acid lactone (PCL),polyhydroxybutyrate (PHB), glycolic amyl (PHV), PHB and PHV copolymer(PHBV), and poly lactic acid (PLA)-polyethylene glycol (PEG) copolymers(PLEG).

In embodiments, the topical compositions disclosed herein can be in theform of transdermal patches. The transdermal patches can be in anyconventional form such as, for example, a strip, a gauze, a film, andthe like. Patch material may be nonwoven or woven (e.g., gauzedressing). Layers may also be laminated during processing. It may benonocclusive or occlusive, but the latter is preferred for backinglayers. The patch is preferably hermetically sealed for storage (e.g.,foil packaging). The patch can be held onto the skin and components ofthe patch can be held together using various adhesives. For example, thetransdermal patch can be in the form of a band-aid type device, or itmay be packaged in a small metal or plastic “cup”, which is strappedonto the appropriate site using an adhesive, tape, or an outer fabric orleather strap, similar to that worn as part of a watch. The entire patchmay be disposable or may be refillable.

In embodiments, the topical compositions disclosed herein can be coatedon bandages, mixed with bioadhesives, or included in dressings.

A wide variety of methods may be used for preparing the formulationsdescribed herein. Broadly speaking, the formulations may be prepared bycombining together the components of the formulation, as describedherein, at a temperature and for a time sufficient to provide apharmaceutically acceptable composition. For example, in someembodiments, the topical compositions components may be dissolved,suspended, dispersed or otherwise mixed in a selected carrier orvehicle, at an effective concentration such that the condition to betreated is relieved or ameliorated.

Methods of Using Topical Compositions to Treat Atopic Dermatitis

Embodiments of the invention are directed to methods of treating atopicdermatitis in a subject comprising topically administering to thesubject in need thereof a topical composition containing tapinarof asdescribed herein, wherein one or more symptom of atopic dermatitis isimproved. In some embodiments, the atopic dermatitis is mild tomoderate.

Embodiments of the invention are directed to methods of treating atopicdermatitis in a subject comprising topically administering once a day tothe subject in need thereof a topical composition containing about 0.5%tapinarof as described herein, wherein one or more symptom of atopicdermatitis is improved. In some embodiments, the atopic dermatitis ismild to moderate.

Embodiments of the invention are directed to methods of treating atopicdermatitis in a subject comprising topically administering once a day tothe subject in need thereof a topical composition containing about 1.0%tapinarof as described herein, wherein one or more symptom of atopicdermatitis is improved. In some embodiments, the atopic dermatitis ismild to moderate.

Embodiments of the invention are directed to methods of treating atopicdermatitis in a subject comprising topically administering twice a dayto the subject in need thereof a topical composition containing about0.5% tapinarof as described herein, wherein one or more symptom ofatopic dermatitis is improved. In some embodiments, the atopicdermatitis is mild to moderate.

Embodiments of the invention are directed to methods of treating atopicdermatitis in a subject comprising topically administering twice a dayto the subject in need thereof a topical composition containing about1.0% tapinarof as described herein, wherein one or more symptom ofatopic dermatitis is improved. In some embodiments, the atopicdermatitis is mild to moderate.

In embodiments described herein, the topically administering of thetopical composition includes application to the skin of the body, arms,legs, back, chest, buttocks, neck, scalp, fingernails, or toenails wherethe atopic dermatitis lesions are present (or “affected area”). Thetopically administering of the topical composition includes applyingenough of the composition to completely cover each lesion with a thinlayer. In embodiments described herein, administration of the topicalcomposition requires that the subject lightly rub the cream into theskin until it is no longer visible.

In embodiments described herein, the subject is an adult or anadolescent. In embodiments described herein, the adolescents is age 12to 17. In embodiments described herein, the subject is younger than 18years of age. In embodiments described herein, the subject is youngerthan 2 years of age. In embodiments described herein, the subject is 18years of age or older. In embodiments described herein, the subject isbetween the ages of 18 to 75 years old.

In embodiments described herein, the subject has been diagnosed withatopic dermatitis having a percent body surface area (BSA) affected ofabout 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%,about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%,about 34%, or about 35%. In preferred embodiments, the subject has beendiagnosed with atopic dermatitis having a percent body surface area(BSA) affected of about 3% to about 20%. In embodiments describedherein, body surface area (BSA) excludes the scalp, palms of the handsand soles of the feet.

In embodiments described herein, the subject has been diagnosed withatopic dermatitis having an Investigator Global Assessment (IGA) ofabout 3, or about 4. In embodiments described herein, the subject hasbeen diagnosed with mild to moderate atopic dermatitis having anInvestigator Global Assessment (IGA) of greater than or equal to 3.

In embodiments described herein, the topical composition is administeredonce daily for up to 24 weeks. In embodiments described herein, thetopical composition is administered once daily for 24 weeks. Inembodiments described herein, the topical composition is administeredonce daily for up to 12 weeks. In embodiments described herein, thetopical composition is administered once daily for 12 weeks. Inembodiments described herein, the topical composition is administeredonce daily for up to 8 weeks. In embodiments described herein, thetopical composition is administered once daily for 8 weeks. Inembodiments described herein, the topical composition is administeredonce daily for up to 6 weeks. In embodiments described herein, thetopical composition is administered once daily for 6 weeks. Inembodiments described herein, the topical composition is administeredonce daily for up to 4 weeks. In embodiments described herein, thetopical composition is administered once daily for 4 weeks. Inembodiments described herein, the topical composition is administeredonce daily until the atopic dermatitis is resolved.

In embodiments described herein, the topical composition is administeredtwice daily for up to 24 weeks. In embodiments described herein, thetopical composition is administered twice daily for 24 weeks. Inembodiments described herein, the topical composition is administeredtwice daily for up to 12 weeks. In embodiments described herein, thetopical composition is administered twice daily for 12 weeks. Inembodiments described herein, the topical composition is administeredtwice daily for up to 8 weeks. In embodiments described herein, thetopical composition is administered twice daily for 8 weeks. Inembodiments described herein, the topical composition is administeredtwice daily for up to 6 weeks. In embodiments described herein, thetopical composition is administered twice daily for 6 weeks. Inembodiments described herein, the topical composition is administeredtwice daily for up to 4 weeks. In embodiments described herein, thetopical composition is administered twice daily for 4 weeks. Inembodiments described herein, the topical composition is administeredtwice daily until the atopic dermatitis is resolved.

In embodiments described herein, the one or more symptom of atopicdermatitis is measured according to an assessment selected fromInvestigator Global Assessment (IGA) score, daily Itch/Pruritus numericrating scale, Eczema Area and Severity Index (EASI), total severityscore, percent body surface area (BSA) affected, sleep quality,dry/rough skin, red/discolored skin, flaky skin, visual analogue scale(VAS) for sleep, visual analogue scale (VAS) for itch, and patientreported outcomes.

In embodiments described herein, the Investigator's Global Assessment(IGA) is used for assessing the current state/severity of a subject'sAD, also referred to as vIGA-AD™ (Validated Investigator GlobalAssessment for Atopic Dermatitis), a scale developed by Eli Lilly andCompany and atopic dermatitis experts, including International EczemaCouncil advisors and Industry experts, for use in clinical trials. Ituses a static 5-point morphological assessment of overall diseaseseverity, as determined by the investigator, using the clinicalcharacteristics of erythema, infiltration, papulation, oozing, andcrusting as guidelines. In certain embodiments, the IGA is made daily,weekly, or monthly and without reference to previous scores. The scoringsystem ranges from 0 (=Clear) to 4 (=Severe). A score of 0 (Clear) hasthe following morphological description: no inflammatory signs of atopicdermatitis (no erythema, no induration/papulation, no lichenification,no oozing/crusting), and post-inflammatory hyperpigmentation and/orhypopigmentation may be present. A score of 1 (Almost Clear) has thefollowing morphological description: barely perceptible erythema, barelyperceptible induration/papulation, and/or minimal lichenification, andno oozing or crusting. A score of 2 (Mild) has the followingmorphological description: slight but definite erythema (pink), slightbut definite induration/papulation, and/or slight but definitelichenification, and no oozing or crusting. A score of 3 (Moderate) hasthe following morphological description: clearly perceptible erythema(dull red), clearly perceptible induration/papulation, and/or clearlyperceptible lichenification, and oozing and crusting may be present. Ascore of 4 (Severe) has the following morphological description: markederythema (deep or bright red), marked induration/papulation, and/ormarked lichenification, disease is widespread in extent, and oozing orcrusting may be present. In embodiments described herein, the subject'sInvestigator Global Assessment (IGA) score improved by about 1 grade,about 2 grades, about 3 grades, about 4 grades, or about 5 grades. Inembodiments described herein, the subject's Investigator GlobalAssessment (IGA) score improved by about 2 grades. In embodimentsdescribed herein, the subject's Investigator Global Assessment (IGA)score improved to a score of about 0 or about 1. In embodimentsdescribed herein, the subject's Investigator Global Assessment (IGA)score improved to a score of about 1 or almost clear. In certainembodiments, the subject achieved a score of about 0 or about 1 by week1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week10, week 11, or week 12. In certain embodiments, the subject achieved a2-grade improvement by week 1, week 2, week 3, week 4, week 5, week 6,week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14,week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22,week 23, or week 24. In embodiments described herein, the subject hassustained improvement of PGA score after treatment has ended. Inembodiments described herein, the subject has sustained improvement ofPGA score about 1 week, about 2 weeks, about 3 weeks, about 4 weeks,about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks,about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18weeks, about 19 weeks, about 20 weeks, or up to 52 weeks after treatmenthas ended. In embodiments described herein, the subject does notexperience worsening of PGA score about 1 week, about 2 weeks, about 3weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks,about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17weeks, about 18 weeks, about 19 weeks, about 20 weeks, or up to 52 weeksafter treatment has ended.

In embodiments described herein, administration of the topicalcomposition to a subject having severe atopic dermatitis is effectivelytreated wherein the subject achieved a “Clear” or “Almost Clear” ratingaccording to the PGA with at least a 2 point improvement. In embodimentsdescribed herein, administration of the topical composition to a subjecthaving moderate atopic dermatitis is effectively treated wherein thesubject achieved a “Clear” or “Almost Clear” rating according to the PGAwith at least a 2 point improvement. In embodiments described herein,administration of the topical composition to a subject having mildatopic dermatitis is effectively treated wherein the subject achieved a“Clear” rating according to the PGA.

Pruritus is the most frequent symptom of AD and potentially has thegreatest effect on quality of life. In embodiments described herein, thedaily Itch/Pruritus numeric rating scale is subject-reported andobtained from the itch item on the Daily Sign and Symptom SeverityDiary. In embodiments described herein, the subject's Itch/Pruritusnumeric rating scale is improved by about 1 point, about 2 points, about3 points, about 4 points, or about 5 points. In embodiments describedherein, the subject's Itch/Pruritus numeric rating scale is improved by3 points.

The assessment of the % BSA affected is an estimate of the percentage oftotal involved skin with atopic dermatitis. The extent of BSA affectedby AD is a general indicator of disease severity. In embodimentsdescribed herein, one percent body surface area (1% BSA) is theequivalent of the total palmar surface of the palm plus 5 digits. The %BSA affected is calculated using the following regional body areas: Headand neck; Trunk, includes internal axillae and groin; Upper extremities,includes arms, external axillae, and hands; and Lower extremities,includes legs, buttocks, and feet. In embodiments described herein, bodysurface area (BSA) excludes the scalp, palms of the hands and soles ofthe feet. The % BSA assessment is utilized in the EASI. The % BSAaffected by atopic dermatitis is evaluated from 0 to 100%. Inembodiments described herein, the subject's percent body surface area(BSA) affected is decreased. In certain embodiments, the subjectachieved a decrease in the % BSA affected by week 1, week 2, week 3,week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week20, week 21, week 22, week 23, or week 24. In embodiments describedherein, the subject has sustained improvement of % BSA affected aftertreatment has ended. In embodiments described herein, the subject hassustained improvement of percent body surface area (BSA) affected about1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks,about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks,about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19weeks, about 20 weeks, or up to 52 weeks after treatment has ended. Inembodiments described herein, the subject does not experience worseningof % BSA affected about 1 week, about 2 weeks, about 3 weeks, about 4weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks,about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18weeks, about 19 weeks, about 20 weeks, or up to 52 weeks after treatmenthas ended.

In embodiments described herein, the Eczema Area and Severity Index(EASI) is measured using a scoring system for assessing the severity ofAD that takes into account the overall severity of erythema,infiltration/papulation, excoriation, and lichenification, as well asthe extent of BSA affected with AD. The 4 clinical signs are each gradedon a 4-point scale (0 to 3) for each of the 4 specified body regions(head and neck, upper extremities, lower extremities, and trunk). TheEASI is a static assessment made without reference to previous scores.In embodiments described herein, the subject's Eczema Area and SeverityIndex (EASI) is improved by about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,about 95%, or about 100%. In embodiments described herein, the subject'sEczema Area and Severity Index (EASI) is improved by greater than orequal to 25%, greater than or equal to 50%, or greater than or equal to75%. In embodiments described herein, the subject's Eczema Area andSeverity Index (EASI) is improved by greater than or equal to 50%. Inembodiments described herein, the subject's Eczema Area and SeverityIndex (EASI) is improved by greater than or equal to 75%. In certainembodiments, the subject achieved a greater than 50% improvement in EASIby week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week17, week 18, week 19, week 20, week 21, week 22, week 23, or week 24. Incertain embodiments, the subject achieved a greater than 75% improvementin EASI by week 1, week 2, week 3, week 4, week 5, week 6, week 7, week8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, orweek 24. In certain embodiments, the subject achieved a greater than 90%improvement in EASI by week 1, week 2, week 3, week 4, week 5, week 6,week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14,week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22,week 23, or week 24. In embodiments described herein, the subject hassustained improvement of EASI after treatment has ended. In embodimentsdescribed herein, the subject has sustained improvement of EASI about 1week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks,about 20 weeks, or up to 52 weeks after treatment has ended. Inembodiments described herein, the subject does not experience worseningof EASI about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks,about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks,about 19 weeks, about 20 weeks, or up to 52 weeks after treatment hasended.

In embodiments described herein, the total severity score (TSS) isdetermined by measuring a single target lesion measuring at least 3 cmat baseline and was representative of subject disease, but not locatedon hands, feet or genitalia. The single target lesion selected to assessefficacy in treating a discrete area rather than an overall average ofall areas. For the single target lesion, the severity of erythema,induration/papulation, lichenification, oozing/crusting, and scaling wasassessed on a 4-point scale and TSS was calculated. The maximum scorewas 15, with higher scores indicating more severe disease. Inembodiments described herein, the subject's total severity scoreimproved by about 1 point, about 2 points, 3 points, about 4 points,about 5 points, about 6 points, about 7 points, about 8 points, about 9points, about 10 points, about 11 points, about 12 points, about 13points, about 14 points, or about 15 points. In certain embodiments, thesubject achieved an improvement in total severity score by week 1, week2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week19, week 20, week 21, week 22, week 23, or week 24. In embodimentsdescribed herein, the subject has sustained improvement of totalseverity score after treatment has ended. In embodiments describedherein, the subject has sustained improvement of total severity scoreabout 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks,about 19 weeks, about 20 weeks, or up to 52 weeks after treatment hasended. In embodiments described herein, the subject does not experienceworsening of total severity score about 1 week, about 2 weeks, about 3weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks,about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17weeks, about 18 weeks, about 19 weeks, about 20 weeks, or up to 52 weeksafter treatment has ended.

In embodiments described herein, patient reported outcomes were measuredusing the Daily Sign and Symptom Severity Diary and the ExpandedPatient-Oriented Eczema Measure (POEM).

In some embodiments, different quality of life scales are utilized toassess patient improvement through Patient Reported Outcome (PRO)measures. EQ-5D-5L is a five level scale to define general healthlevels, for example having no problems, having slight problems, havingmoderate problems, having severe problems and being unable to do/havingextreme problems. Children's Dermatology Life Quality Index (CDLQI)includes physical symptoms, such as itching and sleep loss, as well aspsychosocial questions regarding friendships, bullying, schoolperformance, sports participation, and enjoyment of vacation.Dermatology Life Quality Index (DLQI) inquires about skin symptoms,feelings of embarrassment, and how skin disease has affected day-to-dayactivities, working and social life. Infant's Dermatology Quality ofLife (IDQOL) includes questions regarding an infant or young child'sdifficulties with mood, sleep, bathing, dressing, play, mealtimes, otherfamily activities, and treatment Dermatitis Family Impact (DFI) isdesigned to be completed by a caretaker of the child, usually a parent,and consists of 10 questions related to housework, food preparation andfeeding, sleep, family leisure activity, shopping, expenditure, fatigue,emotional distress and relationships. The PROMIS Itch-Mood and SleepShort Form 8a assesses mood and sleep related quality of life impairmentfrom itch (pruritus) in adults (18+), it is universal rather thandisease specific and assesses the impact of itch over the past 7 daysand includes 18 items. In embodiments described herein, the subjectscore in one of more PRO, such as EQ-5D-5L, CDLQI, DLQI, IDQOL, DFI,and/or PROMIS Itch-Mood and Sleep improves.

In embodiments described herein, the self-administered Daily Sign andSymptom Severity Diary assesses the severity of 11 disease-related signsand symptoms: 1.) skin that is itchy, 2.) discolored, 3.) bleeding, 4.)oozing, 5.) cracked, 6.) scaly, 7.) flaky, 8.) dry/rough, 9.) painful,10.) burning, and 11.) stinging. Response options are on an 11-pointnumeric rating scale (NRS) and range from 0 (Absent) to 10 (WorstImaginable). In embodiments described herein, the recall period was theprevious 24 hours. In embodiments described herein, the subject'sassessment of itchy skin, red/discolored skin, bleeding, weeping oroozing skin, cracked skin, scaly skin, flaky skin, dry or rough skin,painful skin, burning skin, or burning skin, each improved by about 1point, about 2 points, 3 points, about 4 points, about 5 points, about 6points, about 7 points, about 8 points, about 9 points, about 10 points,or about 11 points. In certain embodiments, the subject reported animprovement on one or more symptoms assessed by the Daily Sign andSymptom Severity Diary by week 1, week 2, week 3, week 4, week 5, week6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14,week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22,week 23, or week 24. In embodiments described herein, the subject hassustained improvement of one or more symptoms assessed by the Daily Signand Symptom Severity Diary after treatment has ended. In embodimentsdescribed herein, the subject has sustained improvement of one or moresymptoms assessed by the Daily Sign and Symptom Severity Diary about 1week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks,about 20 weeks, or up to 52 weeks after treatment has ended. Inembodiments described herein, the subject does not experience worseningof one or more symptoms assessed by the Daily Sign and Symptom SeverityDiary about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks,about 19 weeks, about 20 weeks, or up to 52 weeks after treatment hasended.

In embodiments described herein, the subject assessed disease severityusing the self-administered Expanded Patient-Oriented Eczema Measure(POEM). In embodiments described herein, the Expanded POEM assessedseven symptoms: 1.) skin that is itchy, 2.) bleeding, 3.)weeping/oozing, 4.) cracked, 5.) flaking, 6.) dry/rough, and 7.)disturbed sleep; measured using a 5-point scale of frequency ofoccurrence during the previous week. The 3 questions to assess sleepquality were directed to the frequency of waking at night difficultyfalling asleep due to the atopic dermatitis. Individual responses werescored from 0 to 4. Improvement in sleep and improvement in itch werealso measured using a visual analogue scale (VAS). In embodimentsdescribed herein, the subject's assessment of itchy skin, bleeding,weeping/oozing, cracked skin, flaking skin, dry/rough skin, anddisturbed sleep each improved by about 1 point, about 2 points, 3points, or about 4 points. In embodiments described herein, thesubject's assessment of sleep quality is improved. In embodimentsdescribed herein, the subject's assessment of disturbed sleep improved.In certain embodiments, the subject reported an improvement on one ormore symptoms assessed by POEM by week 1, week 2, week 3, week 4, week5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13,week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21,week 22, week 23, or week 24. In embodiments described herein, thesubject has sustained improvement of one or more symptoms assessed bythe POEM after treatment has ended. In embodiments described herein, thesubject has sustained improvement of one or more symptoms assessed bythe POEM about 1 week, about 2 weeks, about 3 weeks, about 4 weeks,about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks,about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18weeks, about 19 weeks, about 20 weeks, or up to 52 weeks after treatmenthas ended. In embodiments described herein, the subject does notexperience worsening of one or more symptoms assessed by the POEM about1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks,about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks,about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19weeks, about 20 weeks, or up to 52 weeks after treatment has ended.

In embodiments described herein, the one or more symptoms improved byabout 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6weeks, about 7 weeks, or about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks,about 20 weeks, or up to 52 weeks after of administering the topicalcomposition. In embodiments described herein, the one or more symptomsimproved by about 2 weeks of administering the topical composition. Inembodiments described herein, the one or more symptoms improved by about4 weeks of administering the topical composition. In embodimentsdescribed herein, the one or more symptoms improved by about 8 weeks ofadministering the topical composition. In embodiments described herein,the one or more symptoms improved by about 12 weeks of administering thetopical composition.

In some embodiments, it was surprisingly found that the topicalcomposition may produce long lasting effects on the skin and may modifythe long-term course of atopic dermatitis. Specifically, in certainembodiments, the improvement of the symptoms seen during administrationof the topical composition may be maintained long after the finaladministration of the topical composition. In embodiments describedherein, the one or more symptoms remain improved about 1 week, about 2weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks,or up to 52 weeks after administration of the composition has ceased. Inembodiments described herein, the one or more symptoms remain improvedabout 2 weeks after administration of the topical composition hasceased. In embodiments described herein, the one or more symptoms remainimproved about 3 weeks after administration of the topical compositionhas ceased. In embodiments described herein, the one or more symptomsremain improved about 4 weeks after administration of the topicalcomposition has ceased. In embodiments described herein, the one or moresymptoms remain improved about 8 weeks after administration of thetopical composition has ceased. In embodiments described herein, the oneor more symptoms remain improved about 12 weeks after administration ofthe topical composition has ceased. In embodiments described herein, theone or more symptoms remain improved about 16 weeks after administrationof the topical composition has ceased. In embodiments described herein,the one or more symptoms remain improved about 20 weeks afteradministration of the topical composition has ceased.

It was surprisingly found that the topical composition may produce longlasting effects on the skin and may modify the long-term course ofatopic dermatitis. Specifically, in certain embodiments, the symptoms donot worsen after the final administration of the topical composition. Inembodiments described herein, the one or more symptoms do not worsenabout 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 12 weeks, about 13 weeks, about 14 weeks,about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19weeks, about 20 weeks, or up to 52 weeks after administration of thetopical composition has ceased. In embodiments described herein, the oneor more symptoms do not worsen about 2 weeks after administration of thetopical composition has ceased. In embodiments described herein, the oneor more symptoms do not worsen about 3 weeks after administration of thetopical composition has ceased. In embodiments described herein, the oneor more symptoms do not worsen about 4 weeks after administration of thetopical composition has ceased. In embodiments described herein, the oneor more symptoms do not worsen about 8 weeks after administration of thetopical composition has ceased. In embodiments described herein, the oneor more symptoms do not worsen about 12 weeks after administration ofthe topical composition has ceased. In embodiments described herein, theone or more symptoms do not worsen about 16 weeks after administrationof the topical composition has ceased. In embodiments described herein,the one or more symptoms do not worsen about 20 weeks afteradministration of the topical composition has ceased.

In embodiments described herein, the topical composition exhibits lowsystemic absorption following topical application. In embodimentsdescribed herein, the topical composition exhibits no accumulation withrepeat dosing. Systemic absorption of tapinarof is measured in plasma.In embodiments described herein, plasma concentration of tapinarof isbelow the limit of detection (LOD) when measured at 1, 2, 4, 6, 8 and 24hours following once daily application of the topical compositiondescribed herein. In embodiments described herein, plasma concentrationof tapinarof is below the limit of detection (LOD) when measured at 1,2, 4, 6, 8 and 24 hours following twice daily application of the topicalcomposition described herein. In some embodiments, the mean AUC_([0-24])is about 23.4 to about 2.2 h*ng/mL. In some embodiments, the meanAUC_([0-24]) is about 10.5 to about 1.5 h*ng/mL.

In embodiments described herein, the topical composition isnon-stinging.

In embodiments described herein, the topical composition is moreeffective than pimecrolimus (Elidel™), tacrolimus (Protopic™),crisaborole (Eucrisa™), or desonide (Verdeso™ or Desonate™).

In embodiments described herein, the topical composition is administeredin an initial dosing regimen followed by a maintenance dosing regimen.In embodiments described herein, the initial dosing regimen is about 1week to about 24 weeks in duration. In embodiments described herein, themaintenance dosing regimen is about 1 week to about 24 weeks induration. In embodiments described herein, the topical compositionadministered in the initial dosing regimen contains 1% tapinarof. Inembodiments described herein, the topical composition administered inthe maintenance dosing regimen contains 0.5% tapinarof.

In embodiments, the method may include the co-administration ofadditives, other second active agents or enzymes as described herein. Inembodiments, co-administration may be at the same time, substantiallythe same time, before or after administration of the topicalcompositions described herein.

In embodiments, the additives may be selected from the group consistingof vitamins, cosmetic peptides, oil control agents, sensation modifyingagents, skin lightening agents, hydrating compositions, a sunblockagent, a compound that absorbs or reflects UV photons, other skin careagents, a second active agent and combinations thereof, as describedherein.

In some embodiments, administration of the composition is by topicalapplication, transdermal, percutaneous, or microneedle injection.

In embodiments, the composition is administered by microneedleinjection. Microneedle is a hollow needle having an exposed height ofbetween about 0 and 1 mm and a total length of between about 0.3 mm toabout 2.5 mm. Preferably, the microneedle is a hollow needle having alength of less than about 2.5 mm. Most preferably, the microneedle is ahollow needle having a length of less than about 1.7 mm. The compositioncomprising therapeutic cells and extracellular matrix component aredelivered into the skin to a depth of at least about 0.3 mm and no morethan about 2.5 mm by the microneedle.

In some embodiments, the topical composition can be applied to the skinone, two, three, four, five or more times each day, and applying can becarried out for a period of at least 1 month, 2 months, 3 months, 4months, 6 months, 8 months or 12 months.

In such embodiments, the topical composition can be applied to the skinone, two, three, four, five or more times each day, and applying can becarried out for a period of at least 1 month, 2 months, 3 months, 4months, 6 months, 8 months or 12 months.

In some embodiments, the topical composition may be administered once,as needed, once daily, twice daily, three times a day, once a week,twice a week, every other week, every other day, or the like for one ormore dosing cycles. A dosing cycle may include administration for about1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks,about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10weeks. After this cycle, a subsequent cycle may begin approximately 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks later. The treatment regimemay include 1, 2, 3, 4, 5, or 6 cycles, each cycle being spaced apart byapproximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

Methods of Using Topical Compositions to Treat Psoriasis

Embodiments of the invention are directed to methods of treating chronicplaque psoriasis in a subject comprising topically administering to thesubject in need thereof a topical composition containing tapinarof asdescribed herein, wherein one or more symptom of psoriasis is improved.In some embodiments, the chronic plaque psoriasis is mild to moderate.

Embodiments of the invention are directed to methods of treating chronicplaque psoriasis in a subject comprising topically administering once aday to the subject in need thereof a topical composition containingabout 0.5% tapinarof as described herein, wherein one or more symptom ofpsoriasis is improved. In some embodiments, the chronic plaque psoriasisis mild to moderate.

Embodiments of the invention are directed to methods of treating chronicplaque psoriasis in a subject comprising topically administering once aday to the subject in need thereof a topical composition containingabout 1.0% tapinarof as described herein, wherein one or more symptom ofpsoriasis is improved. In some embodiments, the chronic plaque psoriasisis mild to moderate.

Embodiments of the invention are directed to methods of treating chronicplaque psoriasis in a subject comprising topically administering twice aday to the subject in need thereof a topical composition containingabout 0.5% tapinarof as described herein, wherein one or more symptom ofpsoriasis is improved. In some embodiments, the chronic plaque psoriasisis mild to moderate.

Embodiments of the invention are directed to methods of treating chronicplaque psoriasis in a subject comprising topically administering twice aday to the subject in need thereof a topical composition containingabout 1.0% tapinarof as described herein, wherein one or more symptom ofpsoriasis is improved. In some embodiments, the chronic plaque psoriasisis mild to moderate.

Embodiments of the invention are directed to methods of treating chronicplaque psoriasis in a subject comprising topically administering to thesubject in need thereof a topical composition containing tapinarof asdescribed herein, wherein skin type does not affect the efficacy of thetreatment. In some embodiments, the chronic plaque psoriasis is mild tomoderate. In some embodiments, the skin type is measured using theFitzpatrick scale, wherein the subject's skin type is selected from thegroup consisting of Fitzpatrick skin type I, Fitzpatrick skin type II,Fitzpatrick skin type III, Fitzpatrick skin type IV, Fitzpatrick skintype V, and Fitzpatrick skin type VI. Fitzpatrick scale is a numericalclassification schema for human skin color. The following list shows thesix categories of the Fitzpatrick scale: Type I—always burns, never tans(palest, freckles); Type II—usually burns, tans minimally; TypeIII—sometimes mild burn, tans uniformly; Type IV—burns minimally, alwaystans well (moderate brown); Type V—very rarely burns, tans very easily(dark brown); or Type VI—never burns (deeply pigmented dark brown todarkest brown). In some embodiments, a method of treating chronic plaquepsoriasis in a subject having Fitzpatrick skin type I comprisingtopically administering to the subject in need thereof a topicalcomposition containing tapinarof as described herein. In someembodiments, a method of treating chronic plaque psoriasis in a subjecthaving Fitzpatrick skin type II comprising topically administering tothe subject in need thereof a topical composition containing tapinarofas described herein. In some embodiments, a method of treating chronicplaque psoriasis in a subject having Fitzpatrick skin type IIIcomprising topically administering to the subject in need thereof atopical composition containing tapinarof as described herein. In someembodiments, a method of treating chronic plaque psoriasis in a subjecthaving Fitzpatrick skin type IV comprising topically administering tothe subject in need thereof a topical composition containing tapinarofas described herein. In some embodiments, a method of treating chronicplaque psoriasis in a subject having Fitzpatrick skin type V comprisingtopically administering to the subject in need thereof a topicalcomposition containing tapinarof as described herein. In someembodiments, a method of treating chronic plaque psoriasis in a subjecthaving Fitzpatrick skin type VI comprising topically administering tothe subject in need thereof a topical composition containing tapinarofas described herein.

In embodiments described herein, the topically administering of thetopical composition includes application to the skin of the body, arms,legs, back, chest, buttocks, neck, scalp, fingernails, or toenails wherethe plaque psoriasis lesions are present (or “affected area”). Thetopically administering of the topical composition includes applyingenough of the topical composition to completely cover each lesion with athin layer. In embodiments described herein, administration of thetopical composition requires that the subject lightly rub the cream intothe skin until it is no longer visible.

In embodiments described herein, the subject has been diagnosed withchronic plaque psoriasis and has had stable disease for at least 6months, at least 7 months, at least 8 months, at least 9 months, atleast 10 months, at least 11 months, or at least 12 months. In preferredembodiments, the subject has been diagnosed with chronic mild tomoderate plaque psoriasis and has had stable disease for at least 6months.

In embodiments described herein, the subject is younger than 18 years ofage. In embodiments described herein, the subject is 18 years of age orolder. In embodiments described herein, the subject is between the agesof 18 to 75 years old.

In embodiments described herein, the subject has been diagnosed withchronic plaque psoriasis having a percent body surface area (BSA)affected of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%,about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%,about 33%, about 34%, or about 35%. In preferred embodiments, thesubject has been diagnosed with chronic plaque psoriasis having apercent body surface area (BSA) affected of about 3% to about 20%. Inembodiments described herein, body surface area (BSA) excludes thescalp, palms of the hands and soles of the feet.

In embodiments described herein, the subject has been diagnosed withchronic plaque psoriasis having a Physician Global Assessment (PGA)score of about 2, about 3, or about 4. In embodiments described herein,the subject has been diagnosed with chronic mild to moderate plaquepsoriasis having a Physician Global Assessment (PGA) score of greaterthan or equal to 2. A PGA score of 2 is a diagnosis of mild plaquepsoriasis. A PGA score of 3 is a diagnosis of moderate plaque psoriasis.A PGA score of 4 is a diagnosis of severe plaque psoriasis.

In embodiments described herein, the topical composition is administeredonce daily for up to 24 weeks. In embodiments described herein, thetopical composition is administered once daily for 24 weeks. Inembodiments described herein, the topical composition is administeredonce daily for up to 12 weeks. In embodiments described herein, thetopical composition is administered once daily for 12 weeks. Inembodiments described herein, the topical composition is administeredonce daily for up to 8 weeks. In embodiments described herein, thetopical composition is administered once daily for 8 weeks. Inembodiments described herein, the topical composition is administeredonce daily for up to 6 weeks. In embodiments described herein, thetopical composition is administered once daily for 6 weeks. Inembodiments described herein, the topical composition is administeredonce daily for up to 4 weeks. In embodiments described herein, thetopical composition is administered once daily for 4 weeks. Inembodiments described herein, the topical composition is administeredonce daily until the chronic plaque psoriasis is resolved.

In embodiments described herein, the topical composition is administeredtwice daily for up to 24 weeks. In embodiments described herein, thetopical composition is administered twice daily for 24 weeks. Inembodiments described herein, the topical composition is administeredtwice daily for up to 12 weeks. In embodiments described herein, thetopical composition is administered twice daily for 12 weeks. Inembodiments described herein, the topical composition is administeredtwice daily for up to 8 weeks. In embodiments described herein, thetopical composition is administered twice daily for 8 weeks. Inembodiments described herein, the topical composition is administeredtwice daily for up to 6 weeks. In embodiments described herein, thetopical composition is administered twice daily for 6 weeks. Inembodiments described herein, the topical composition is administeredtwice daily for up to 4 weeks. In embodiments described herein, thetopical composition is administered twice daily for 4 weeks. Inembodiments described herein, the topical composition is administeredtwice daily until the chronic plaque psoriasis is resolved.

In embodiments described herein, the topical composition comprisingtapinarof is administered before the administration of apremilast(Otezla™).

In embodiments described herein, the one or more symptom of chronicpsoriasis is measured according to an assessment selected from PhysicianGlobal Assessment (PGA) score, Psoriasis Area and Severity Index (PASI),target lesion grading, Itch/Pruritus numeric rating scale (NRS), percentbody surface area (BSA) affected, Psoriasis Symptom Diary (PSD),Dermatology Quality of Life Index (DLQI), or SF-36 questionnaire.

In embodiments described herein, the Physician Global Assessment (PGA)is used to assess the current state/severity of a subject's psoriasis.It is a static 5-point morphological assessment of overall diseaseseverity, as determined by the investigator, using the clinicalcharacteristics of erythema, plaque thickness, and scaling asguidelines. In certain embodiments, the PGA is assessed daily, weekly,or monthly and without reference to previous scores. The scoring systemincludes: Score of 0 represents clear skin with no signs of psoriasis,postinflammatory hyperpigmentation may be present; Score of 1 representsalmost clear skin with no thickening, normal to pink coloration, no tominimal focal scaling; Score of 2 represents mild psoriasis with justdetectable to mild thickening, pink to light red coloration,predominantly fine scaling; Score of 3 represents moderate psoriasiswith clearly distinguishable to moderate thickening, dull to bright red,clearly distinguishable erythema, moderate scaling; and Score of 4represents severe psoriasis with severe thickening with hard edges,bright to deep dark red coloration, severe/coarse scaling coveringalmost all or all lesions. In embodiments described herein, thesubject's Physician Global Assessment (PGA) score improved by about 1grade, about 2 grades, about 3 grades, about 4 grades, or about 5grades. In embodiments described herein, the subject's Physician GlobalAssessment (PGA) score improved by about 2 grades. In embodimentsdescribed herein, the subject's Physician Global Assessment (PGA) scoreimproved to a score of about 0 or clear. In embodiments describedherein, the subject's Physician Global Assessment (PGA) score improvedto a score of about 1 or almost clear. In certain embodiments, thesubject achieved a score of about 0 or about 1 by week 1, week 2, week3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, orweek 12. In certain embodiments, the subject achieved a 2-gradeimprovement by week 1, week 2, week 3, week 4, week 5, week 6, week 7,week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15,week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23,or week 24. In embodiments described herein, the subject has sustainedimprovement of PGA score after treatment has ended. In embodimentsdescribed herein, the subject has sustained improvement of PGA scoreabout 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks,about 19 weeks, about 20 weeks, or up to 52 weeks after treatment hasended. In embodiments described herein, the subject does not experienceworsening of PGA score about 1 week, about 2 weeks, about 3 weeks, about4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks,about 18 weeks, about 19 weeks, about 20 weeks, or up to 52 weeks aftertreatment has ended.

In embodiments described herein, administration of the topicalcomposition to a subject having severe plaque psoriasis is effectivelytreated wherein the subject achieved a “Clear” or “Almost Clear” ratingaccording to the PGA with at least a 2 point improvement. In embodimentsdescribed herein, administration of the topical composition to a subjecthaving moderate plaque psoriasis is effectively treated wherein thesubject achieved a “Clear” or “Almost Clear” rating according to the PGAwith at least a 2 point improvement. In embodiments described herein,administration of the topical composition to a subject having mildplaque psoriasis is effectively treated wherein the subject achieved a“Clear” rating according to the PGA.

The assessment of the % BSA affected is an estimate of the percentage oftotal involved skin with psoriasis. The extent of BSA affected bypsoriasis is a general indicator of disease severity. In embodimentsdescribed herein, one percent body surface area (1% BSA) is theequivalent of the total palmar surface of the palm plus 5 digits. The %BSA affected is calculated using the following regional body areas: Headand neck; Trunk, includes internal axillae and groin; Upper extremities,includes arms, external axillae, and hands; and Lower extremities,includes legs, buttocks, and feet. In embodiments described herein, bodysurface area (BSA) excludes the scalp, palms of the hands and soles ofthe feet. The % BSA assessment is utilized in the PASI. The % BSAaffected by psoriasis is evaluated from 0 to 100%. In embodimentsdescribed herein, the subject's percent body surface area (BSA) affectedis decreased. In certain embodiments, the subject achieved a decrease inthe % BSA affected by week 1, week 2, week 3, week 4, week 5, week 6,week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14,week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22,week 23, or week 24. In embodiments described herein, the subject hassustained improvement of % BSA affected after treatment has ended. Inembodiments described herein, the subject has sustained improvement ofpercent body surface area (BSA) affected about 1 week, about 2 weeks,about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks,about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks,or up to 52 weeks after treatment has ended. In embodiments describedherein, the subject does not experience worsening of % BSA affectedabout 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks,about 19 weeks, about 20 weeks, or up to 52 weeks after treatment hasended.

In embodiments described herein, the Psoriasis Area and Severity Index(PASI) is used to assess the severity of psoriasis that takes intoaccount the overall severity of erythema (redness), thickness(induration), and scale (desquamation), as well as the extent of BSAaffected with psoriasis. The 3 clinical signs are each graded on a 5point scale (0 to 4) and the % BSA affected is scored on a 7-point scale(0 to 6) for each of the 4 specified body regions (head, upperextremities, trunk, and lower extremities). The individual scores aremultiplied by a weighted factor for each body region; the sum of thesescores gives the overall PASI score. Higher scores indicate more severedisease. PASI is a static assessment made without reference to previousscores. In embodiments described herein, the subject's Psoriasis Areaand Severity Index (PASI) is improved by about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, about 95%, or about 100%. In embodiments describedherein, the subject's Psoriasis Area and Severity Index (PASI) isimproved by greater than or equal to 25%, greater than or equal to 50%,greater than or equal to 75%, or greater than or equal to 90%. Inembodiments described herein, the subject's Psoriasis Area and SeverityIndex (PASI) is improved by greater than or equal to 50%. In embodimentsdescribed herein, the subject's Psoriasis Area and Severity Index (PASI)is improved by greater than or equal to 75%. In embodiments describedherein, the subject's Psoriasis Area and Severity Index (PASI) isimproved by greater than or equal to 90%. In certain embodiments, thesubject achieved a greater than 50% improvement in PASI by week 1, week2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week19, week 20, week 21, week 22, week 23, or week 24. In certainembodiments, the subject achieved a greater than 75% improvement in PASIby week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week17, week 18, week 19, week 20, week 21, week 22, week 23, or week 24. Incertain embodiments, the subject achieved a greater than 90% improvementin PASI by week 1, week 2, week 3, week 4, week 5, week 6, week 7, week8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, orweek 24. In embodiments described herein, the subject has sustainedimprovement of PASI after treatment has ended. In embodiments describedherein, the subject has sustained improvement of PASI about 1 week,about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks,about 20 weeks, or up to 52 weeks after treatment has ended. Inembodiments described herein, the subject does not experience worseningof PASI about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks,about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks,about 19 weeks, about 20 weeks, or up to 52 weeks after treatment hasended.

In embodiments described herein, the target lesion grading is determinedby measuring a single target lesion at baseline to assess efficacy intreating a discrete area rather than an overall average of all areas.For that single target lesion, the severity of erythema, scaling, andplaque thickness is assessed on a 5-point scale ranging from 0 (=none)to 4 (=severe). The maximum score was 15, with higher scores indicatingmore severe disease. In embodiments described herein, the subject'starget lesion grading improved by about 1 point, about 2 points, 3points, about 4 points, about 5 points, about 6 points, about 7 points,about 8 points, about 9 points, about 10 points, about 11 points, about12 points, about 13 points, about 14 points, or about 15 points. Incertain embodiments, the subject achieved an improvement in targetlesion grading by week 1, week 2, week 3, week 4, week 5, week 6, week7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15,week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23,or week 24. In embodiments described herein, the subject has sustainedimprovement of target lesion grading after treatment has ended. Inembodiments described herein, the subject has sustained improvement oftarget lesion grading about 1 week, about 2 weeks, about 3 weeks, about4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks,about 18 weeks, about 19 weeks, about 20 weeks, or up to 52 weeks aftertreatment has ended. In embodiments described herein, the subject doesnot experience worsening of target lesion grading about 1 week, about 2weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks,about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks,or up to 52 weeks after treatment has ended.

In embodiments described herein, the daily Itch/Pruritus severity issubject-reported and obtained as a numeric rating scale (NRS) from theitch item on the Psoriasis Symptom Diary (PSD). In embodiments describedherein, the subject's Itch/Pruritus severity is improved by about 1point, about 2 points, 3 points, about 4 points, or about 5 points. Inembodiments described herein, the subject's Itch/Pruritus severity isimproved by 3 points. In certain embodiments, the subject achieved animprovement in daily Itch/Pruritus numeric rating scale (NRS) by week 1,week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10,week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18,week 19, week 20, week 21, week 22, week 23, or week 24. In embodimentsdescribed herein, the subject has sustained improvement of Itch/Pruritusseverity after treatment has ended. In embodiments described herein, thesubject has sustained improvement of Itch/Pruritus severity about 1week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks,about 20 weeks, or up to 52 weeks after treatment has ended. Inembodiments described herein, the subject does not experience worseningof Itch/Pruritus severity about 1 week, about 2 weeks, about 3 weeks,about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks,about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17weeks, about 18 weeks, about 19 weeks, about 20 weeks, or up to 52 weeksafter treatment has ended.

In embodiments described herein, patient reported outcomes were measuredusing the Psoriasis Symptom Diary (PSD) which assesses dailyself-reports of psoriasis symptoms and the functional impact related tothe underlying pathophysiology of the disease. Questions asked about howsevere and how bothersome various symptoms were to the subject. Thesymptoms assessed include 1) severity of flaky skin, 2) bother of flakyskin, 3) severity of dry skin, 4) bother of dry skin, 5) severity ofbleeding, 6) bother of bleeding, 7) severity of itching, 8) bother ofitching, 9) stinging, 10) burning, 11) pain from skin cracking, 12)psoriasis-related pain, 13) scaling, 14) noticeability of color, 15)need to hide skin, 16) avoidance of activities, and 17) overallembarrassment. Each item was rated using an 11-point numeric ratingscale (NRS) and range from 0 (Absent) to 10 (Worst Imaginable). Inembodiments described herein, the recall period was the previous 24hours. In embodiments described herein, the subject's assessment offlaky skin, bother of flaky skin, severity of dry skin, bother of dryskin, severity of bleeding, bother of bleeding, severity of itching,bother of itching, stinging, burning, pain from skin cracking,psoriasis-related pain, scaling, noticeability of color, need to hideskin, avoidance of activities, and overall embarrassment, each improvedby about 1 point, about 2 points, about 3 points, about 4 points, about5 points, about 6 points, about 7 points, about 8 points, about 9points, about 10 points, or about 11 points. In certain embodiments, thesubject reported an improvement on one or more symptoms assessed by thePSD by week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8,week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16,week 17, week 18, week 19, week 20, week 21, week 22, week 23, or week24. In embodiments described herein, the subject has sustainedimprovement of one or more symptoms assessed by the PSD after treatmenthas ended. In embodiments described herein, the subject has sustainedimprovement of one or more symptoms assessed by the PSD about 1 week,about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks,about 20 weeks, or up to 52 weeks after treatment has ended. Inembodiments described herein, the subject does not experience worseningof one or more symptoms assessed by the PSD about 1 week, about 2 weeks,about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks,about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks,or up to 52 weeks after treatment has ended.

In embodiments described herein, subjects record changes using theDermatology Quality of Life Index (DLQI) questionnaire. The DLQI is asimple dermatology-specific 10 question validated questionnaire toassess the impact of the disease on a subject's quality of life. TheDLQI has become an important outcome measure in dermatology clinicaltrials and is the most frequently used instrument in studies ofrandomized controlled trials in dermatology. The DLQI can be analyzed asa total score (where a higher score indicates greater impairment inquality of life) and can also be scored for the following dimensions:Symptoms and Feelings (items 1 and 2), Daily Activities (items 3 and 4),Leisure (items 5 and 6), Work and School (item 7), PersonalRelationships (items 8 and 9), and Treatment (item 10). In certainembodiments, the subject reported an improvement on the impact of one ormore daily activities assessed by the DLQI by week 1, week 2, week 3,week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week20, week 21, week 22, week 23, or week 24. In embodiments describedherein, the subject has sustained improvement on the impact of one ormore daily activities assessed by the DLQI after treatment has ended. Inembodiments described herein, the subject has sustained improvement ofone or more daily activities assessed by the DLQI about 1 week, about 2weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks,about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks,or up to 52 weeks after treatment has ended. IV. In embodimentsdescribed herein, the subject does not experience worsening of one ormore daily activities assessed by the DLQI about 1 week, about 2 weeks,about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks,about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks,or up to 52 weeks after treatment has ended.

In embodiments described herein, subjects self-administer the 36 ItemShort Form Survey (SF-36). The SF-36 is a questionnaire about physicalfunctioning; bodily pain; role limitations due to physical health orpersonal or emotional problems; emotional well-being; socialfunctioning; energy/fatigue; general health perceptions; and perceivedchange in health. Eight domain scores and 2 summary component (physicaland mental) scores can be calculated; higher scores represent betterhealth status. In certain embodiments, the subject reported animprovement in the physical component score assessed by the SF-36questionnaire by week 1, week 2, week 3, week 4, week 5, week 6, week 7,week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15,week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23,or week 24. In certain embodiments, the subject reported an improvementin the mental component score assessed by the SF-36 questionnaire byweek 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9,week 10, week 11, week 11, week 12, week 13, week 14, week 15, week 16,week 17, week 18, week 19, week 20, week 21, week 22, week 23, or week24. In embodiments described herein, the subject has sustainedimprovement in the physical component score and/or the mental componentscore assessed by the SF-36 questionnaire after treatment has ended. Inembodiments described herein, the subject has sustained improvement inin the physical component score and/or the mental component scoreassessed by the SF-36 questionnaire about 1 week, about 2 weeks, about 3weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks,about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17weeks, about 18 weeks, about 19 weeks, about 20 weeks, or up to 52 weeksafter treatment has ended. In embodiments described herein, the subjectdoes not experience worsening of the physical component score and/or themental component score assessed by the SF-36 questionnaire about 1 week,about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks,about 20 weeks, or up to 52 weeks after treatment has ended.

In embodiments described herein, the one or more symptoms improved byabout 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks,about 20 weeks, or up to 52 weeks after administering the topicalcomposition. In embodiments described herein, the one or more symptomsimproved by about 2 weeks of administering the topical composition. Inembodiments described herein, the one or more symptoms improved by about4 weeks of administering the topical composition. In embodimentsdescribed herein, the one or more symptoms improved by about 8 weeks ofadministering the topical composition. In embodiments described herein,the one or more symptoms improved by about 12 weeks of administering thetopical composition.

In some embodiments, it was surprisingly found that the topicalcomposition may produce long lasting effects on the skin and may modifythe long-term course of chronic plaque psoriasis. Specifically, incertain embodiments, the improvement of the symptoms seen duringadministration of the topical composition may be maintained long afterthe final administration of the topical composition. In embodimentsdescribed herein, the one or more symptoms remain improved about 1 week,about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks,about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20weeks, or up to 52 weeks after administration of the topical compositionhas ceased. In embodiments described herein, the one or more symptomsremain improved about 2 weeks after administration of the topicalcomposition has ceased. In embodiments described herein, the one or moresymptoms remain improved about 3 weeks after administration of thetopical composition has ceased. In embodiments described herein, the oneor more symptoms remain improved about 4 weeks after administration ofthe topical composition has ceased. In embodiments described herein, theone or more symptoms remain improved about 8 weeks after administrationof the topical composition has ceased. In embodiments described herein,the one or more symptoms remain improved about 12 weeks afteradministration of the topical composition has ceased. In embodimentsdescribed herein, the one or more symptoms remain improved about 16weeks after administration of the topical composition has ceased. Inembodiments described herein, the one or more symptoms remain improvedabout 20 weeks after administration of the topical composition hasceased.

It was surprisingly found that the topical composition may produce longlasting effects on the skin and may modify the long-term course ofchronic plaque psoriasis. Specifically, in certain embodiments, thesymptoms do not worsen after the final administration of the topicalcomposition. In embodiments described herein, the one or more symptomsdo not worsen about 1 week, about 2 weeks, about 3 weeks, about 4 weeks,about 5 weeks, about 6 weeks, about 12 weeks, about 13 weeks, about 14weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks,about 19 weeks, about 20 weeks, or up to 52 weeks after administrationof the topical composition has ceased. In embodiments described herein,the one or more symptoms do not worsen about 2 weeks afteradministration of the topical composition has ceased. In embodimentsdescribed herein, the one or more symptoms do not worsen about 3 weeksafter administration of the topical composition has ceased. Inembodiments described herein, the one or more symptoms do not worsenabout 4 weeks after administration of the topical composition hasceased. In embodiments described herein, the one or more symptoms do notworsen about 8 weeks after administration of the topical composition hasceased. In embodiments described herein, the one or more symptoms do notworsen about 12 weeks after administration of the topical compositionhas ceased. In embodiments described herein, the one or more symptoms donot worsen about 16 weeks after administration of the topicalcomposition has ceased. In embodiments described herein, the one or moresymptoms do not worsen about 20 weeks after administration of thetopical composition has ceased.

In embodiments described herein, the topical composition exhibits lowsystemic absorption following topical application. In embodimentsdescribed herein, the topical composition exhibits no accumulation withrepeat dosing. Systemic absorption of tapinarof is measured in plasma.In embodiments described herein, plasma concentration of tapinarof isbelow the limit of detection (LOD) when measured at 1, 2, 4, 6, 8 and 24hours following once daily application of the topical compositiondescribed herein. In embodiments described herein, plasma concentrationof tapinarof is below the limit of detection (LOD) when measured at 1,2, 4, 6, 8 and 24 hours following twice daily application of the topicalcomposition described herein. In some embodiments, the mean AUC_([0-24])is about 23.4 to about 2.2 h*ng/mL. In some embodiments, the meanAUC_([0-24]) is about 10.5 to about 1.5 h*ng/mL.

In embodiments described herein, the topical composition is moreeffective than topical corticosteroids, apremilast (Otezla™),calcipotriene and betamethasone dipropionate (Enstilar™), or vitamin D.

In embodiments described herein, the topical composition can be used ina long-term treatment regimen, compared with topical corticosteroidswhich can only be used for 2-4 weeks. In embodiments described herein,the topical composition can be used for greater than 12 weeks.

In embodiments described herein, the topical composition is administeredin an initial dosing regimen followed by a maintenance dosing regimen.In embodiments described herein, the initial dosing regimen is about 1week to about 24 weeks in duration. In embodiments described herein, themaintenance dosing regimen is about 1 week to about 24 weeks induration. In embodiments described herein, the topical compositionadministered in the initial dosing regimen contains 1% tapinarof. Inembodiments described herein, the topical composition administered inthe maintenance dosing regimen contains 0.5% tapinarof.

In embodiments, the method may include the co-administration ofadditives, other second active agents or enzymes as described herein. Inembodiments, co-administration may be at the same time, substantiallythe same time, before or after administration of the topicalcompositions described herein.

In embodiments, the additives may be selected from the group consistingof vitamins, cosmetic peptides, oil control agents, sensation modifyingagents, skin lightening agents, hydrating compositions, a sunblockagent, a compound that absorbs or reflects UV photons, other skin careagents, a second active agent and combinations thereof, as describedherein.

In some embodiments, administration of the composition is by topicalapplication, transdermal, percutaneous, or microneedle injection.

In embodiments, the composition is administered by microneedleinjection. Microneedle is a hollow needle having an exposed height ofbetween about 0 and 1 mm and a total length of between about 0.3 mm toabout 2.5 mm. Preferably, the microneedle is a hollow needle having alength of less than about 2.5 mm. Most preferably, the microneedle is ahollow needle having a length of less than about 1.7 mm. The compositioncomprising therapeutic cells and extracellular matrix component aredelivered into the skin to a depth of at least about 0.3 mm and no morethan about 2.5 mm by the microneedle.

In some embodiments, the topical composition can be applied to the skinone, two, three, four, five or more times each day, and applying can becarried out for a period of at least 1 month, 2 months, 3 months, 4months, 6 months, 8 months or 12 months.

In such embodiments, the topical composition can be applied to the skinone, two, three, four, five or more times each day, and applying can becarried out for a period of at least 1 month, 2 months, 3 months, 4months, 6 months, 8 months or 12 months.

In some embodiments, the topical composition may be administered once,as needed, once daily, twice daily, three times a day, once a week,twice a week, every other week, every other day, or the like for one ormore dosing cycles. A dosing cycle may include administration for about1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks,about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10weeks. After this cycle, a subsequent cycle may begin approximately 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks later. The treatment regimemay include 1, 2, 3, 4, 5, or 6 cycles, each cycle being spaced apart byapproximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore, the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontained within this specification. Various aspects of the presentinvention will be illustrated with reference to the followingnon-limiting examples.

EXAMPLES Example 1—Results of Phase II Clinical Study in AD

This study, which included 247 subjects, was conducted to evaluate theefficacy and safety of a range of concentrations of Tapinarof cream forthe topical treatment of AD in adolescents and adults. Results of thisstudy will be used to select the most appropriate concentration andapplication frequency of Tapinarof cream to evaluate in Phase IIIclinical studies.

The study objectives and the associated endpoints were as described inTable 1.

TABLE 1 Study Objectives and Associated Endpoints Objectives EndpointsPrimary To estimate the relationship Proportion of subjects who had anInvestigator Global between GSK2894512 cream Assessment (IGA) score ofclear or almost clear (0 or 1) concentrations (0.5%, 1%) and at Week 12and a minimum 2-grade improvement in IGA application frequency withscore from Baseline to Week 12 efficacy response, based upon clinicalevaluations in subjects with AD Secondary To estimate the efficacy ofProportion of subjects who achieved an IGA score of 0 GSK2894512 creamor 1 and a minimum 2-grade improvement from Baseline to each study visitProportion of subjects with a minimum 2-grade improvement in IGA scorefrom Baseline to each study visit Proportion of subjects with an IGAscore of 0 or 1 at each study visit Mean change in IGA score fromBaseline to each study visit Proportion of subjects with ≥75%improvement in Eczema Area and Severity Index (EASI75) from Baseline toeach study visit Mean percent change in Eczema Area and Severity Index(EASI) score from Baseline to each study visit Proportion of subjectswith ≥50% improvement in EASI (EASI50) from Baseline to each study visitMean change in EASI score from Baseline to each study visit Mean changein percent of body surface area (% BSA) affected from Baseline to eachstudy visit Mean change in Total Severity Score (TSS) from Baseline toeach study visit Mean percent change in TSS from Baseline to each studyvisit Mean change in individual signs of TSS from Baseline to each studyvisit Mean percent change in individual sign of TSS from Baseline toeach study visit Mean change in weekly average of daily itch/pruritus(numeric rating scale [NRS]) score (based on Item #1 of Daily Sign &Symptom Severity Diary) from Baseline to Week 12 Mean Percent change inweekly average of daily itch/pruritus (NRS) score (based on Item #1 ofDaily Sign & Symptom Severity Diary) from Baseline to Week 12 Proportionof subjects who achieved a minimum 3-point improvement in weekly averageof itch/pruritus (NRS) from Baseline to each study visit To describe thesafety and Incidence, frequency, and nature of AEs and serioustolerability of GSK2894512 adverse events (SAEs) cream Localtolerability scores over time Change over time in clinical laboratorytests and frequency of clinically-significant abnormal test resultsChange over time in vital signs and frequency of clinically-significantabnormal results Incidence and nature of abnormal electrocardiograms(ECGs) To describe the safety and Incidence, frequency, and nature ofAEs and serious tolerability of GSK2894512 adverse events (SAEs) creamLocal tolerability scores over time Change over time in clinicallaboratory tests and frequency of clinically-significant abnormal testresults Change over time in vital signs and frequency ofclinically-significant abnormal results Incidence and nature of abnormalelectrocardiograms (ECGs) Other To describe the effect of Change inexpanded Patient-Oriented Eczema Measure GSK2894512 cream on (POEM)items from Baseline to each study visit subject-reported outcomes Changein weekly average of Daily Sign and Symptom Severity Diary score fromBaseline to each study visit Subject impression of severity of eczemasymptoms and overall change in severity of eczema symptoms and overallchange in itch/pruritus from Baseline to Week 12 To characterize thepopulation Population estimates of PK parameters as data permitpharmacokinetics (PK) of GSK2894512 after topical application ofGSK2894512 cream To explore the relationship Relationship between creamconcentration and/or between topical exposure (i.e., % BSA treated andchanges in systemic exposure as data cream concentration and % BSApermit treated), efficacy, and/or safety, Relationship between systemicexposure and changes in and systemic exposure of efficacy (e.g., IGAscore) and/or safety endpoints, as GSK2894512, as data permit.appropriate To estimate the duration of Proportion of subjects who hadan IGA score of 0 or 1 response of GSK2894512 cream at Week 12 and aminimum 2-grade improvement in IGA score from Baseline to Week 12 andwho maintained that response at 2 and 4 weeks post-treatment Proportionsof subjects who achieved improvement with respect to individualsecondary efficacy endpoints at Week 12 and maintained the improvementat 2 and 4 weeks post-treatment, as appropriate To explore themeasurement Evaluate the reliability, validity, and ability to detectproperties of the Daily Sign and change of the Daily Sign and SymptomSeverity Diary, Symptom Severity Diary including the itch/pruritus NRS

Study Design

This was a multicenter (United States, Canada, and Japan), randomized,double-blind (Sponsor-unblind), vehicle-controlled, 6-arm,parallel-group, dose-finding study in adolescent and adult subjects withAD.

The study consisted of 3 periods: up to 4 weeks screening, 12 weeksdouble-blind treatment, and 4 weeks post-treatment Follow-up. Studyvisits occurred at Screening; Baseline; Weeks 1, 2, 4, 8, and 12 duringthe treatment period; and 2 and 4 weeks after the last application ofstudy treatment (i.e., at Weeks 14 and 16). Additional visits couldoccur, as needed, to follow-up on any skin reactions or ongoing AEs. Asubject's total duration of study participation was approximately 16 to20 weeks.

Two concentrations of Tapinarof cream (0.5% and 1%) and a vehiclecontrol were evaluated following application to all AD lesions (excepton the scalp) once or twice daily for 12 weeks. There were no planneddose adjustments during the study. It was expected that approximately270 adolescent and adult subjects with AD would be screened to achieve228 randomized subjects (1:1:1:1:1:1; N=3 8 for each of the 6 treatmentgroups) and approximately 204 evaluable subjects overall. At least 30subjects were to be randomized in Japan to achieve at least 24 evaluableJapanese subjects. To ensure an adequate number of adolescents (aged 12to 17 years) versus adults were represented in the overall studypopulation, enrollment was limited to approximately 65% of either agegroup.

The ITT Population was to include all randomized subjects. Subjects whoprematurely discontinued from the study were not replaced.

Efficacy was assessed by using a 5-point static Investigator GlobalAssessment (IGA) (0-4 scale), the Eczema Area and Severity Index (EASI),percent of body surface area (% BSA) involvement, severity of AD signsusing a Total Severity Score (TSS), and by subject-reporteditch/pruritus severity using a numeric rating scale (NRS) (from theDaily Sign and Symptom Severity Diary). Additional subject-reportedoutcomes included the expanded Patient-Oriented Eczema Measure (POEM), aDaily Sign and Symptom Severity Diary, and subject impression ofseverity of eczema symptoms and overall change in severity of eczemasymptoms and overall change in itch/pruritus items. There was also aninvestigator global impression of change item.

Safety was assessed by the monitoring and recording of all AEs andserious adverse events (SAEs); evaluation of local (application site)tolerability; monitoring of hematology (including peripheral bloodimmunophenotyping and immunoglobulins), clinical chemistry, and vitalsigns; and the performance of ECGs and physical examinations.

An independent data monitoring committee (IDMC) was utilized in thisstudy to ensure external objective medical and/or statistical review ofsafety issues.

An unblinded, interim analysis was carried out (database lock: 11 Jul.2016) to identify the appropriate drug concentration and topicalapplication frequency of GSK2894512 for use in Phase III clinicalstudies. The interim analysis was conducted when approximately 100subjects had completed the Week 8 visit. The access to unblindedinformation was limited and defined a priori in a study resultsdissemination plan.

Discussion of Study Design

The randomized, double-blind (Sponsor-unblind), vehicle-controlled studydesign was selected to minimize the potential for subjective biasrelated to possible identification of which subjects are receivingactive treatment and to minimize selection and allocation bias bybalancing potential prognostic factors. The study was conducted atmultiple study centers to enhance the possibility of inclusion of awider range of population groups and to subsequently increasegeneralizability of the results.

Clinical studies in skin conditions have historically shown a notablevehicle (as well as placebo) response rate, which could be attributableto the effects of skin moisturization or to the increased emphasis onproper skin care while participating in a clinical study. A vehiclecontrol group was included in this study to provide a control forcomparison and to ensure study assay sensitivity for characterization ofthe safety and efficacy profile of Tapinarof cream.

The predicted maximum systemic exposure to Tapinarof in this study wasexpected to be lower than the no observed adverse effects level (NOAEL)identified in nonclinical toxicology studies. Exposure predicted basedon in vitro flux data and topical minipig relative bioavailabilityshowed a lesser systemic exposure for 1% cream Formulation F versusFormulations C or E. This provided a safety margin of 4- to 8-fold forpredicted area under the concentration-time curve (AUC) for 24 hours(0-24) and 4- to 6-fold for predicted maximum observed concentration(Cmax) for 1% cream (Formulation F) applied twice daily when comparedwith the NOAEL obtained from the rat subcutaneous 3 mg/kg/day, 13-weektoxicology study (99 ng. h/mL for AUC₍₀₋₂₄₎ and 31.6 ng/mL for Cmax).

The treatment duration was 12 weeks. Previous studies of Tapinarof cream(using Formulation C) showed some efficacy within the first 14 days oftreatment and increasing efficacy over 12 weeks of treatment. The12-week treatment endpoint in this study was expected to be an adequateduration of treatment to measure response.

Inclusion Criteria

A subject was eligible for inclusion in this study only if all of thefollowing criteria applied: 1. Male or female aged 12 years to 65 years,inclusive, at the time of informed consent; 2. Diagnosis of ADfulfilling the specified diagnostic criteria and having activeinflammation; 3. Body surface area involvement >5% and <35%, excludingscalp, at Screening and Baseline; 4. An IGA of AD score >3 at Baseline;5. At least 1 target lesion that measured at least 3 cm² at Screeningand Baseline, Must have been representative of the subject's diseasestate, but not located on the hands, feet or genitalia; 6. A femalesubject was eligible to participate if she was not pregnant (asconfirmed by a negative urine human chorionic gonadotrophin [hCG] test),not lactating, and when at least one of the following conditionsapplied: a. Non-reproductive potential defined as: pre-menopausalfemales with 1 of the following: documented tubal ligation, documentedhysteroscopic tubal occlusion procedure with follow-up confirmation ofbilateral tubal occlusion, hysterectomy, documented dilateraloophorectomy, postmenopausal was defined as 12 months of spontaneousamenorrhea (in questionable cases a blood sample with simultaneousfollicle stimulating hormone [FSH] and estradiol levels consistent withmenopause [refer to laboratory reference ranges for confirmatorylevels]). Females on hormone replacement therapy (HRT) and whosemenopausal status was in doubt were required to use 1 of the highlyeffective contraception methods if they wished to continue their HRTduring the study. Otherwise, they had to discontinue HRT to allowconfirmation of post-menopausal status prior to study enrollment. b.Reproductive potential and agreed to follow 1 of the options listed inthe Modified List of Highly Effective Methods for Avoiding Pregnancy inFemales of Reproductive Potential (FRP) (see Protocol, Appendix 5) from30 days prior to the first dose of study medication and until after thelast dose of study medication and completion of the Follow-up visit. Theinvestigator was responsible for ensuring that subjects understood howto properly use these methods of contraception.

Exclusion Criteria

A subject was not eligible for inclusion in this study if any of thefollowing criteria applied: 1. Unstable course of AD (spontaneouslyimproving or rapidly deteriorating) as determined by the investigatorover the previous 4 weeks prior to Baseline; 2. Concurrent conditionsand history of other diseases: a. Immunocompromised (e.g., lymphoma,acquired immunodeficiency syndrome, Wiskott-Aldrich Syndrome) or had ahistory of malignant disease within 5 years before the Baseline visit).b. Chronic or acute infection requiring treatment with systemicantibiotics, antivirals, antiparasitics, antiprotozoals, or antifungalswithin 4 weeks before the Baseline visit. c. Active acute bacterial,fungal, or viral (e.g., herpes simplex, herpes zoster, chicken pox) skininfection within 1 week before the Baseline visit. d. Any otherconcomitant skin disorder (e.g., generalized erythroderma such asNetherton's Syndrome or psoriasis), pigmentation, or extensive scarringthat in the opinion of the investigator could interfere with theevaluation of AD lesions or compromise subject safety. e. Presence of ADlesions only on the hands or feet without prior history of involvementof other classical areas of involvement such as the face or the folds.f. Other types of eczema. 3. A history or ongoing serious illness ormedical, physical, or psychiatric condition(s) that, in theinvestigator's opinion, could have interfered with the subject'scompletion of the study. 4. Known hypersensitivity to excipients. 5.Current or chronic history of liver disease, known hepatic or biliaryabnormalities (with the exception of Gilbert's syndrome or asymptomaticgallstones), presence of hepatitis B surface antigen (HBsAg), orpositive hepatitis C antibody test result within 3 months of Screening.6. Liver function tests: alanine aminotransferase (ALT) >2× upper limitof normal (ULN); alkaline phosphatase and bilirubin >1.5×ULN (isolatedbilirubin >1.5×ULN was acceptable if bilirubin was fractionated anddirect bilirubin <35%). 7. QT interval corrected for heart rate(QTc) >450 msec or QTc >480 msec for subjects with bundle branch block.8. The QTc is the QT interval corrected for heart rate, with machineoverread. The QTc was to be based on a single ECG obtained over a briefrecording period. If QTc was outside of the threshold value, triplicateECGs could be performed with the QTc values averaged. (Refer toProtocol, Section 7.4.5 for information on QTc correction formula.) 9.Ultraviolet (UV) light therapy or prolonged exposure to natural orartificial sources of UV radiation (e.g., sunlight or tanning booth)within 4 weeks prior to the Baseline visit and/or intention to have suchexposure during the study, which was thought by the investigator topotentially impact the subject's AD. 10. Used any of the followingtreatments within the indicated washout period before the Baselinevisit: a. 12 weeks or 5 half-lives (whichever was longer)—biologicagents (e.g., 18 weeks for omalizumab). b. 8 weeks—cyclosporin,methotrexate, azathioprine, or other systemic immunosuppressive orimmunomodulating agents, (e.g., mycophenolate or tacrolimus). c. 4weeks—systemic corticosteroids or adrenocorticotropic hormone analogs.d. 2 weeks—topical treatments: corticosteroids, calcineurin inhibitors,or coal tar (on the body). e. 2 weeks—immunizations; sedatingantihistamines (nonsedating antihistamines were permitted). f. 1week—topical antibiotics, antibacterial cleansing body wash/soap ordiluted sodium hypochlorite “bleach” baths. 11. Participated in aclinical study and received an investigational product within thefollowing time period prior to the Baseline visit: 4 weeks, 5half-lives, or twice the duration of the biological effect of theinvestigational product (whichever was longer). 12. History of alcoholor other substance abuse within the last 2 years. 13. Participated in aprevious study using Tapinarof (or WBI-1001).

Investigational Product and Reference Therapy: The term ‘studytreatment’ is used throughout this document to describe the product(i.e., Tapinarof or vehicle) received by subject as per the protocoldesign, as shown in Table 2.

TABLE 2 Investigational Product and Reference Therapy DrugDose/Form/Route Frequency/Duration Tapinarof 1% (10 mg/g), cream,topically BID, 12 weeks Tapinarof 1% (10 mg/g), cream, topically QD, 12weeks Tapinarof 0.5% (5 mg/g), cream, topically BID, 12 weeks Tapinarof0.5% (5 mg/g), cream, topically QD, 12 weeks Vehicle 0%, cream,topically BID, 12 weeks Vehicle 0%, cream, topically QD, 12 weeks

The list of excipients include are propylene glycol, diethylene glycolmonoethyl ether, polysorbate 80, medium chain triglycerides, emulsifyingwax non-ionic, polyoxyl stearyl ether 2, polyoxyl stearyl ether 20,benzoic acid, butylated hydroxytoluene, purified water, sodium citrate,citric acid monohydrate, and edetate disodium.

Primary Endpoint

The primary endpoint was the proportion of subjects who had an IGA scoreof clear or almost clear (0 or 1) at Week 12 and a minimum 2-gradeimprovement in IGA score from Baseline to Week 12.

Investigator's Global Assessment: The IGA is a clinical tool forassessing the current state/severity of a subject's AD. It is a static5-point morphological assessment of overall disease severity, asdetermined by the investigator, using the clinical characteristics oferythema, infiltration, papulation, oozing, and crusting as guidelines.At each specified time point, the IGA was made without reference toprevious scores. Scoring system ranges from 0 (=Clear) to 4 (=Severe).

Secondary Endpoints

Secondary endpoints were the following: 1. Proportion of subjects whoachieved an IGA score of 0 or 1 and a minimum 2-grade improvement fromBaseline to each study visit; 2. Proportion of subjects with a minimum2-grade improvement in IGA score from Baseline to each study visit; 3.Proportion of subjects with an IGA score of 0 or 1 at each study visit;4. Mean change in IGA score from Baseline to each study visit; 5.Proportion of subjects with >75% improvement in EASI (EASI75) fromBaseline to each study visit; 6. Mean percent change in EASI score fromBaseline to each study visit; 7. Proportion of subjects with >50%improvement in EASI (EASI50) from Baseline to each study visit; 8. Meanchange in EASI score from Baseline to each study visit; 9. Mean changein % BSA affected from Baseline to each study visit; 10. Mean change inTSS from Baseline to each study visit; 11. Mean percent change in TSSfrom Baseline to each study visit; 12. Mean change in individual sign ofTSS from Baseline to each study visit; 13. Mean percent change inindividual signs of TSS from Baseline to each study visit; 14. Meanchange in weekly average of daily itch/pruritus (NRS) score (based onItem #1 of Daily Sign & Symptom Severity Diary) from Baseline to Week12; 15. Mean Percent change in weekly average of daily itch/pruritus(NRS) score (based on Item #1 of Daily Sign & Symptom Severity Diary)from Baseline to Week 12; 16. Proportion of subjects who achieved aminimum 3-point improvement in weekly average of itch/pruritus (NRS)from Baseline to each study visit.

Eczema Area and Severity Index: The EASI scoring system is a standardclinical tool for assessing the severity of AD that takes into accountthe overall severity of erythema, infiltration/papulation, excoriation,and lichenification, as well as the extent of BSA affected with AD. The4 clinical signs are each graded on a 4-point scale (0 to 3) for each ofthe 4 specified body regions (head and neck, upper extremities, lowerextremities, and trunk). The EASI is a static assessment made withoutreference to previous scores.

Body Surface Area: The extent of BSA affected by AD is a generalindicator of disease severity and was measured throughout the study. Theextent of BSA to which study treatment was applied was also recorded.For the purpose of approximate clinical estimation, the total palmarsurface of the palm plus 5 digits was assumed to be approximatelyequivalent to 1% BSA.

Total Severity Score: A single target lesion that measured at least 3 cmat Screening and Baseline and was representative of subject disease, butnot located on hands, feet or genitalia, was selected at Baseline toassess efficacy in treating a discrete area rather than an overallaverage of all areas. For that lesion, the severity of erythema,induration/papulation, lichenification, oozing/crusting, and scaling wasassessed on a 4-point scale and TSS was calculated. The maximum scorewas 15, with higher scores indicating more severe disease.

Investigator Impression of Change Item: This was a single item thatasked the investigator to rate the change from Baseline in the subject'soverall AD symptoms. Response options ranged from “1=very improved” to“7=very worse”. Results will also be used as a clinical anchor inanalyses of the minimally-important differences in the Daily Sign andSymptom Severity Diary, including itch/pruritus.

Pruritus/Itch Severity: Pruritus is the most frequent symptom of AD andpotentially has the greatest effect on quality of life. Subject-reporteditch severity was obtained from the itch item from the Daily Sign andSymptom Severity Diary.

Other Efficacy Endpoints

Other efficacy endpoints were as follows: Relationship between creamconcentration and/or % BSA treated and changes in systemic exposure, asdata permitted; Proportions of subjects who achieved an IGA score of 0or 1 at Week 12 and a minimum 2-grade improvement from Baseline to Week12 and who maintained the improvement at 2 and 4 weeks post-treatment;Proportions of subjects who achieved improvement with respect toindividual secondary efficacy endpoints at Week 12 and maintained theimprovement at 2 and 4 weeks post-treatment, as appropriate; To evaluatethe reliability, validity, and ability to detect change of the DailySign and Symptom Severity Diary, including the itch/pruritus NRS item;Endpoint related to systemic exposure: Relationship between systemicexposure and changes in efficacy (e.g., IGA score) and/or safetyendpoints, as appropriate

Pharmacokinetics: A total of 5 blood samples for PK analysis ofGSK2894512 were collected from each subject over the clinic visits atWeeks 1, 2, 4, 8, and 12. Plasma analysis was performed under themanagement of Bioanalytical Science and Toxicokinetics, DMPK, GSK.

Health Outcomes

Endpoints related to subject-reported outcomes were: Subject impressionof severity of eczema symptoms and overall change in severity of eczemasymptoms and overall change in itch/pruritus from Baseline to Week 12;change in expanded POEM items from Baseline to each study visit; changein weekly average of Daily Sign and Symptom Severity Diary score fromBaseline to each study visit.

In order to evaluate symptoms and symptom impact, subjects completed aSubject Impression of Severity and Change questionnaire, the expandedPOEM, as well as a Daily Sign and Symptom Severity Diary to record ADsymptoms. Each investigator also completed an impression of change item(assessing change in severity of AD symptoms) for each subject.

Subject Impression of Severity and Change Items

At Baseline, treatment, early withdrawal, and Follow-up, subjects wereasked to rate the overall severity of their AD symptoms on a scaleranging from “1=mild” to “4=very severe.”

At Weeks 4, 8, 12, early withdrawal, and Follow-up, the globalimpression of change items asked subjects to rate their change fromBaseline in overall severity of AD symptoms and in overall severity ofitch. Response options ranged from “1=very improved” to “7=very worse.”

Daily Sign and Symptom Severity Diary: The self-administered Daily Signand Symptom Severity Diary (which is based on the content of the POEM)assesses the severity of 11 disease-related signs and symptoms (skinthat is itchy, discolored, bleeding, oozing, cracked, scaly, flaky,dry/rough, painful, burning, and stinging). Response options are on an11-point NRS and range from 0 (Absent) to 10 (Worst Imaginable). Therecall period was the previous 24 hours. Subjects completed the diaryeach day at home using an electronic diary. Adolescents (subjects aged12 to 17) and adults completed the same version of the Daily Sign andSymptom Severity Diary. Question 1 was used to assess itch.

Expanded Patient-Oriented Eczema Measure (POEM): The POEM is aself-assessed measurement tool for monitoring disease activity inchildren and adults with AD. Seven symptoms (skin that is itchy,bleeding, weeping/oozing, cracked, flaking, dry/rough, and disturbedsleep) are measured using a 5-point scale of frequency of occurrenceduring the previous week. The POEM was scored as its original 7-itemmeasure. Individual responses were scored from 0 to 4.

POEM was expanded with an additional 3 questions to assess sleepquality; these were not included in the original published instrument.One question asked about the frequency of waking at night and 2questions asked about difficulty falling asleep. These 3 newly-developedsleep items were analyzed separately.

Primary Efficacy Endpoint

The primary efficacy analyses were conducted on the ITT and PPpopulation, unless otherwise specified.

The study day relative to Day 1 was used as a covariate in the model.

The primary analysis was a repeated measures factorial logisticregression for the primary endpoint (proportion of subjects who have anIGA score of 0 or 1 at Week 12 and a minimum 2-grade improvement in IGAscore from Baseline to Week 12) with covariates for dose (0% forvehicle, 0.5% and 1%), frequency of administration (once or twicedaily), and study day as well as a dose by frequency interaction term.The response at each visit was modelled as repeated measures viainclusion of a random subject effect. Time was included in the modelaccording to an Integrated Two-Component Prediction (ITP) model [Brown2001]. Estimated population mean dose/frequency-response curves alongwith their corresponding 95% confidence bands were provided bothgraphically and in table format for all dose levels and frequencies bytime point of interest. Estimated mean difference in response rate with95% confidence interval between Tapinarof and vehicle cream for BID andQD were provided by time point of interest.

Supportive statistical analysis of primary endpoint based on Japanesesubjects in the ITT population was conducted for 2 frequencies (once ortwice daily) separately using simple logistic regression model withcovariate for dose (0% for vehicle, 0.5% and 1%). The same analysis wasdone for the overall ITT and PP Populations to compare the results ofJapanese population and overall population.

Summary statistics of the number of subjects providing data at therelevant time point, frequency counts and percentages, and 95%confidence interval were provided for the IGA response rate for eachtreatment group at each study visit. Mean and 95% confidence intervalswere provided for the difference of (each BID dose−vehicle BID) and thedifference of (each QD dose−vehicle QD) in IGA response rate at eachvisit.

Secondary Efficacy Endpoints

The secondary efficacy analyses were based on the ITT population, unlessotherwise specified. The following key secondary efficacy analyses werebased on the ITT and PP Populations: proportion of subjects who achievedan IGA score of (0 or 1) and a minimum 2-grade improvement from Baselineto each study visit, proportion of subjects with EASI50 from Baseline toeach study visit, and mean change in EASI score from Baseline to eachstudy visit.

For continuous secondary endpoints, a repeated measures Emax model withITP time component was fitted to the data. All dichotomous secondaryendpoints were modeled in the same logistic regression model describedin the primary statistical analysis. For continuous data, summarystatistics of the mean, standard deviation (SD), median, minimum,maximum, 95% confidence interval and number of observations wereprovided for each treatment group at each study visit. For data ofproportions, summary statistics of the number of subjects providing dataat the relevant time point, frequency counts and percentages, and 95%confidence interval were provided for each treatment group at each studyvisit. Mean and 95% confidence intervals were provided for thedifference of (each BID dose−vehicle BID) and the difference of (each QDdose−vehicle QD) at each visit.

Demographics and Baseline Characteristics

Out of the 247 subjects randomized in this study, 174 (70%) were aged 18to 65 years (adults) and 73 subjects (30%) were aged 12 to 17 years(adolescents).

Overall, mean demographic and Baseline characteristics were comparableacross treatment groups. Most subjects (91%) had a Baseline IGA categoryof “3=moderate”. The mean Baseline EASI score was 11.25 (SD 5.956), themean % BSA affected was 16.91% (SD 10.042), the mean itch/pruritus scorewas 5.5 (SD 2.12), and the mean TSS score was 8.0 (SD 2.27).

By age group, Baseline IGA category for adults and adolescents weresimilar (92%) to the overall population; however, Baseline mean TSSscore was slightly lower for adults (7.9 [SD 2.31]) and slightly higherfor adolescents (8.2 [SD 2.19]).

Note that 2 subjects were included in the database appearing to be 11years old. This was due to only the year of birth being recorded on theeCRF, with the birth date assumed to be the middle of the year (1 June)for the analyses. Subjects born in the first half of 2004 who gaveconsent before June therefore appear as 11-year-olds in the databasedespite actually being 12 years old. These subjects were thereforeincluded in the adolescent group (12-17 years of age) in the statisticalsummaries.

Most Japanese subjects (96%) also had a Baseline IGA category of“3=moderate”; the overall mean EASI score was 12.21 (SD 6.274), mean %BSA affected was 19.25% (SD 9.348), the mean itch/pruritus score was 5.0(SD 2.01), and the mean TSS score (7.4 [SD 1.97]).

The sample size at Baseline for the impression of severity item (242subjects) and itch/pruritus item (226 subjects) was slightly smallerthan the rest of the Baseline characteristics (247 subjects).

Baseline duration of AD in the Japanese population was similar acrosstreatment groups. Similar patterns were also observed by age group. Bysub-group, mean duration was shortest in the Japanese subjects (9.50 [SD8.57] years) followed by the adolescent subjects (11.52 [SD 5.44] years)and adult subjects (21.56 [SD 14.70] years).

A total of 247 subjects (of the 363 subjects originally screened) wererandomized into the study at 32 sites in the United States, eight sitesin Canada, and 13 sites in Japan (ITT analysis population). Of thoserandomized, 191 subjects (77%) completed the study including the Week 16follow-up visit. Overall, mean demographic and baseline characteristicswere comparable across treatment groups (Table 3). Most subjects (91%)had a baseline IGA score of 3 (moderate) and a baseline mean Eczema Areaand Severity Index (EASI) score of 11.3 (SD 6.0). Primary endpoint: IGAresponse rates (defined as IGA score of 0 or 1 and ≥2-grade improvement)at Week 12 were higher with all tapinarof cream groups than vehiclegroups (53% [1% BID]; 46% [1% QD]; 37% [0.5% BID]; 34% [0.5% QD]; 24%[vehicle BID], and 28% [vehicle QD]) and were maintained for 4 weeksafter the end of study treatment (non-responder imputation [NRI]method).

TABLE 3 Baseline subject demographics and characteristics Tapinarof 1%Tapinarof 0.5% Vehicle BID QD BID QD BID QD (n = 40) (n = 41) (n = 43)(n = 41) (n = 42) (n = 40) Mean age, 28.5 (13.9) 31.6 (15.7) 29.0 (15.9)29.3 (14.0) 27.9 (14.7) 29.4 (15.2) years (SD) Aged 12- 11 (28) 13 (32)13 (30) 12 (29) 13 (31) 11 (28) 17 years*, n (%) Aged 18- 29 (73) 28(68) 30 (70) 29 (71) 29 (69) 29 (73) 65 years, n (%) Male sex, 22 (55)17 (41) 26 (60) 19 (46) 19 (45) 23 (58) n (%) IGA 3.1 (0.2) 3.1 (0.3)3.1 (0.3) 3.1 (0.3) 3.1 (0.4) 3.1 (0.3) score, mean (SD) EASI 9.8 (5.1)11.0 (6.1)  13.1 (6.7)  11.4 (5.8)  11.1 (5.8)  11.1 (5.8) score, mean(SD) BSA 14.8 (8.7)  18.7 (11.0) 19.7 (10.5) 17.6 (9.9)  14.5 (9.2) 16.0 (10.3) affected, % (SD) Pruritus 5.2 (2.3) 5.4 (1.9) 5.7 (2.5) 5.7(2.0) 5.1 (2.0) 5.8 (1.9) score, mean (SD)^(†) *Two subjects with age <12 years are included in the 12-17 years sub-group. ^(†)Mean scoresbased on a numerical rating scale (NRS) of 0 ‘absent’ to 10 ‘worstimaginable’. Data provided for the safety analysis population (n = 247).BID, twice daily; BSA, body surface area; EASI, Eczema Area and SeverityIndex; IGA, Investigator Global Assessment; QD, once daily; SD, standarddeviation.

Efficacy Results

Efficacy results are reported using the ITT and PP Population. Resultsare further presented by overall population, adult population (18 to 65years), adolescent population (12 to 17 years), and Japanese population.

Interim Analysis

A “go” decision was reached based on a clinically meaningful efficacyprofile and a well-tolerated safety profile (the analysis was conductedwhen 100 subjects completed the Week 8 visit): Response rates of 35%,74%, 35%, 40% at Week 8 for the proportion of subjects who had an IGAscore of clear or almost clear (0 or 1) and a minimum 2-gradeimprovement in IGA score from Baseline to Week 8 with Tapinarof creamconcentrations 100 BID, 1% QD, 0.5% BID, 0.5% QD, respectively, and 15%for vehicle BID and 27% for vehicle QD. Response rates of 45%, 63%, 59%,35% at Week 8 for the proportion of subjects who had achieved 75%reduction in EASI from Baseline to Week 8 with Tapinarof creamconcentrations 1% BID, 1% QD, 0.5% BID, 0.5% QD, respectively, and 23%for vehicle BID and 33% for vehicle QD. Clinically meaningful itchreduction in weekly average NRS was observed by Week 4 (median) −56.35%,−57.14%, −53.00%, −53.57%, with Tapinarof concentrations 1% BID, 1% QD,0.5% BID, 0.5% QD, respectively, and −2.38% for vehicle BID and −38.33%for vehicle QD. Itch reduction was observed as early as Week 1 in theTapinarof groups. Most frequent AEs (frequency >10% in at least 1treatment arm) were folliculitis, nasopharyngitis, acne, and atopicdermatitis (worsening of pre-existing AD).

Investigator Global Assessment (IGA): The primary efficacy analyses werebased on the ITT and PP Populations, unless otherwise specified. Forsubjects who discontinued investigational product before Week 12, anydata after the last known administration of investigational product wereexcluded from the primary efficacy analyses. The study day relative toDay 1 was used as a covariate in the model. Data after Week 12 and dataafter withdrawal visits were excluded from the efficacy analyses.

The primary objective of this study was to estimate the relationshipbetween Tapinarof cream concentrations (0.5% and 1%) and applicationfrequency (QD or BID) with efficacy response based upon clinicalevaluation in subjects with AD. The primary endpoint was the proportionof subjects who had an IGA score of clear or almost clear (0 or 1) atWeek 12 and a minimum 2-grade improvement in IGA score from Baseline toWeek 12. A subject was defined as having “IGA treatment success” whenthey met the criteria for this endpoint, i.e., an IGA score of clear oralmost clear (0 or 1) and a minimum 2-grade improvement in IGA score.

On average, the probability of achieving an IGA treatment success (IGAscore of clear or almost clear and minimum 2-grade improvement fromBaseline to Week 12) was highest in the 1% active treatment groups(67.7% and 62.6% in the BID and QD groups, respectively), followed bythe 0.5% active treatment groups (28.7% and 18.3% in the BID and QDgroups, respectively. This trend was seen at all visits starting at Week1.

At Week 12, the difference in the probability of IGA responses betweenactive treatment groups and vehicle treatment groups was highest in the1% treatment groups (61.5% and 60.1% in the BID and QD groups,respectively). The difference in the probability of getting an IGAresponse between 0.5% active treatment groups and vehicle groups was22.4% and 15.7% in the BID and QD groups, respectively.

Overall, the primary endpoint analysis showed a higher proportion ofsubjects with IGA treatment success in the 10% BID and 10% QD groups andthe 0.5% BID group than in the vehicle groups at Week 12. Although therewas clear separation between the 0.5% QD group and the vehicle groups atWeek 4 and Week 8, at Week 12 the proportion of subjects with IGAtreatment success leveled off (to 40%) in the 0.5% QD group andincreased sharply in the vehicle QD group (to 44%). The 1% concentrationtreatment groups showed a higher rate of treatment success than therespective (i.e., BID or QD) 0.5% concentration groups.

In the adult population, the primary endpoint analysis showed a higherproportion of subjects in active treatment groups with IGA treatmentsuccess than in vehicle groups at Week 12. The 1% and 0.5% concentrationtreatment groups showed similar rates of success (between 44% and 54%),with rates somewhat higher with BID application than with QDapplication.

In the adolescent population, the primary endpoint analysis showed ahigher proportion of subjects with IGA treatment success in the 1% BIDgroup than in the 1% QD, 0.5% BID, and both vehicle groups, where therewere similar proportions with treatment success. The lowest proportionwas seen in the 0.5% QD group at Week 12. The proportion of subjectswith IGA treatment success was higher in the 1% concentration treatmentgroups than the 0.5% concentration groups.

Overall, the proportion of subjects with IGA treatment success in theTapinarof BID groups continued to increase over time up to Week 12. Inthe QD active groups the proportion increased to Week 8 and thendecreased to Week 12.

In the adult population, the proportion of subjects with treatmentsuccess in the active treatment groups continued to increase over timethrough Week 12, except for the 1% BID group at Week 8 (slight decrease)and the 0.5% QD group at Week 12 (level).

In the adolescent population, the proportion of subjects with treatmentsuccess in the Tapinarof 1% QD group was higher and continued toincrease over time through Week 8. The same pattern was observed for theTapinarof 0.5% QD group, although the proportion of subjects withtreatment success in this group was lower compared to the other groups.The other treatment groups continued to increase up to Week 12. Bothvehicle groups (BID and QD) had a higher proportion of subjects withtreatment success at Week 12 than both 0.5% (BID and QD) treatmentgroups.

IGA secondary endpoint analyses (the proportion of subjects who achievedan IGA score of 0 or 1 and a minimum 2-grade improvement from Baselineto each study visit and maintenance of improvement beyond Week 12)revealed the following: There was an increasing proportion of subjectswho had an IGA score of 0 or 1 at each study visit up to Week 12, exceptfor both (1% and 0.5%) active QD groups, where the proportion decreasedbetween Week 8 and Week 12. The 1% concentration treatment groups showeda higher rate of subjects with treatment success than the corresponding0.5% concentration groups at Week 12. There were no clear differences inthe proportion of subjects who met the primary endpoint and maintainedthe improvement at 2 and 4 weeks post-treatment between active treatmentgroups and vehicle groups.

Ad-hoc Analysis: Investigator Global Assessment (IGA) Non-ResponderImputation (NRI): The efficacy data for the proportion of subjects whohad an IGA score of clear or almost clear (0 or 1) at Week 12 and aminimum 2-grade improvement in IGA score from Baseline to Week 12 werere-analyzed using an NRI to adjust for the higher dropout rates in thevehicle group. Overall, with this method, the higher proportion ofsubjects with treatment success in the active treatment groups than invehicle groups was more clearly defined, as well as the overall betterefficacy for the 1% concentration at each visit. At Week 12, responseswere higher with BID application compared with QD, but this pattern wasnot seen consistently throughout the treatment period.

In the NRI analysis of the adult population, there was a cleardifference between the active and vehicle groups, with similar rates oftreatment success between the 1% and 0.5% concentrations and the BID andQD groups.

In the NRI analysis of the adolescent population, a similar pattern wasseen to the observed cases (OC) analysis, with a strong vehicle BIDresponse throughout treatment and relatively low proportions of subjectswith treatment success in the 0.5% groups.

Eczema Area and Severity Index (EASI): One of the main secondaryobjectives of this study was to estimate the efficacy of Tapinarof creamusing EASI. The main secondary endpoint was the proportion of subjectswith EASI75 from Baseline to each study visit.

On average, the probability of achieving EASI75 at Week 12 was highestin the 1% active treatment groups (86.0% and 80.7% in the BID and QDgroups, respectively), followed by the 0.5% active treatment groups(54.2% and 32.6% in the BID and QD groups, respectively). Theprobability of achieving EASI75 at Week 12 in the vehicle groups was11.6% and 3.7% in the BID and QD groups, respectively. This trend wasseen at all other visits starting at Week 1.

The difference in the probability of achieving EASI75 between activetreatment groups and vehicle treatment groups was highest in the 1%groups (74.5% and 77.0% in the BID and QD groups, respectively). Thedifference in the probability of achieving EASI75 between 0.5% andvehicle groups was 42.6% and 28.9% in the BID and QD groups,respectively.

Generally, after Week 1 to the end of the treatment period, the mainsecondary endpoint analysis showed a higher proportion of subjectsoverall achieving >75% improvement in EASI (EASI75) from Baseline in theactive treatment groups than in the vehicle groups. At Weeks 2 and 4 the1% concentration groups showed a higher rate of responders than the 0.5%concentration groups, but at Weeks 8 and 12 the 0.5% BID group hadsimilar proportions of subjects with improved EASI75 to the 1% groups.

The pattern of the proportion of adult subjects with >75% improvement inEASI from Baseline to each study visit was similar to the overallpopulation, with a higher proportion in active treatment groups showingimprovement than in vehicle groups from Week 2. The adolescent data didnot show such clear trends, with a stronger response in the vehicle BIDgroup and a weaker response in the 0.5% QD group compared with theoverall population.

The proportion of subjects with EASI75 continued to increase in alltreatment groups over time, except for the vehicle QD group betweenWeeks 1 and 2. The frequency of application of Tapinarof, QD or BID, hadno effect on the main secondary endpoint.

Secondary endpoint analyses using EASI percent change and absolutechange over time, maintenance of EASI75, and EASI50 revealed thefollowing: A greater mean percent change reduction in EASI scores fromBaseline to each study visit was observed in active treatment groupsthan in vehicle groups throughout the treatment period. The 1%concentration treatment groups showed a greater mean percentage changereduction than the 0.5% concentration groups in the earlier treatmentphase up to Week 4. At Weeks 8 and 12 the improvements were similar inthe active treatment groups. Similarly, the increasing mean percentchange reduction in EASI scores from Baseline to each study visit wasgreater in active treatment groups than in vehicle groups for both theadult (all visits) and adolescent (up to Week 4) subjects. Generally,the 1% concentration treatment groups showed a slightly greater meanpercentage change reduction than the 0.5% concentration groups, up toWeek 8. The EASI evaluation showed a better efficacy at the earliervisits in the 1% QD group than in the 1% BID group in the adolescentsubjects. The mean change reductions in EASI scores from Baselinecontinued to improve over time with a clear difference between activeand vehicle groups overall. Both the frequency of application ofTapinarof, QD or BID, and the concentration, 1% or 0.5%, had no effecton this parameter. In the BID active treatment groups and the 1% QDgroup, there was an increased proportion of subjects who had a >75%improvement in EASI from Baseline to Week 12, with the best maintenanceof response at 2 and 4 weeks post-treatment seen in the 0.5% BID group.The 3 groups also showed a more sustained improvement than the 0.5% (QD)concentration group in which similar proportions were seen to thevehicle groups. Specifically, 63% (15 of 24) of subjects in the 1% BIDgroup, 57% of subjects (12 of 21) in the 1% QD group, and 82% (18 of 22)of subjects in the 0.5% BID group maintained response from Week 12 toWeek 16. This secondary endpoint result indicates a certain durabilityof the effect of Tapinarof cream after the 12-week treatment period, anda sustained EASI treatment response. The EASI50 results were consistentwith the EASI75 results, except for a stronger vehicle QD response atWeek 12.

Ad-hoc Analysis: Eczema Area and Severity Index (EASI): The efficacydata were analyzed using an NRI method to adjust for the higher dropoutrates in the vehicle group. With NRI a similar trend was seen for EASI75to that in the OC analysis: After 1 week of treatment, there was ahigher proportion of subjects with >75% improvement in EASI in theactive treatment groups than in the vehicle groups. The 1% concentrationtreatment groups showed a higher rate of responders than the 0.5%concentration groups through to Week 4, but at Weeks 8 and 12 the 0.5%BID group had similar proportions with improved EASI75, using NRI. Theadult population demonstrated a consistent trend to the overallpopulation. For adolescent subjects, there was a similar proportion ofsubjects with EASI75 in the vehicle BID group as in the 1% BID, 1% QDand 0.5% BID groups. However, in the 0.5% QD group the proportion ofsubjects with EASI75 was lower, and similar to the proportion in thevehicle QD group. The proportion of subjects with EASI75 responsecontinued to increase over time. The frequency of application ofTapinarof, QD or BID, had no effect on EASI75.

Body Surface Area (BSA): A secondary objective was to assess the meanchange in % BSA affected from Baseline to each study visit. Overall,most subjects had a reduction in % BSA affected over the study period.An increase in the mean change reduction in % BSA affected from Baselineto each study visit was higher in active treatment groups than in thevehicle groups and the increase improved over time. The frequency ofapplication of Tapinarof, QD or BID, had no effect on the mean changereduction in % BSA affected from Baseline to each study visit. A similarpicture was seen in the adult population.

In the adolescent population, the 1% BID and 0.5% BID active treatmentgroups had greater mean change reductions at Weeks 8 and 12 than theactive QD groups; the vehicle BID group had similar mean increases inthe mean change reduction to the active QD treatment groups.

Total Severity Score (TSS): A secondary objective of the study was toseverity of erythema, induration/papulation, lichenification,oozing/crusting, and scaling), and in the individual signs of TSS, inthe individual signs of TSS, from Baseline to each study visit.

Overall, most subjects had a reduction in TSS over the study period. Themean change in TSS from Baseline to each study visit showed animprovement (i.e., reduction) in all treatment groups, but the reductiontended to be larger from Week 2 up to the end of treatment in activetreatment groups than in the vehicle groups. In the summaries by age ofthe mean change in TSS from Baseline to each study visit, this trend wasnot so marked: in the adult population the vehicle QD group had asimilar mean reduction to some of the active treatment groups, and inthe adolescent population this pattern was seen with the vehicle BIDgroup.

Itch/Pruritus Severity: A secondary objective of the study was to assessthe mean change in weekly itch/pruritus NRS item from Baseline to Week12.

Overall, most subjects had a decrease in itch/pruritus symptoms over thestudy period. There was a clear difference in the mean change reductionin itch/pruritus from Baseline to each study visit up to Week 8 betweenactive and vehicle groups; at Week 12, the difference was only apparentfor the BID vehicle group; generally this improvement was maintainedduring the follow-up period. There was no evidence of a dose-relatedresponse among the active groups (frequency or concentration). There wasalso a clear difference between active and vehicle groups from Week 4through Week 12 in the proportion of subjects who achieved a minimum3-point improvement in itch/pruritus. These results were supported inthe ad-hoc NRI summary. Generally, these differences were also seen inthe data by age group, but the response patterns were not always asconsistent.

Investigator Impression of Change: As part of the efficacy assessment,investigators' impression of change in AD symptom severity from Baselineto Week 12 were reported. Responses were rated by investigators as “veryimproved” or “moderately improved” in 80% to 83% of subjects in the 1%concentration groups and 79% to 88% in the 0.5% concentration groups. Inthe “very improved” category, a clear difference was observed betweenactive treatment groups and vehicle groups.

Summaries by age showed that between 71% and 86% of adult subjects wererated by investigators as “very improved” or “moderately improved” inthe active treatment groups compared with less than 70% in the vehiclegroups. In the adolescent population, 90% or more were rated byinvestigators as “very improved” or “moderately improved” in the activetreatment groups compared with just over 80% in the vehicle groups.

Subject-Reported Outcomes: One of the other objectives of this study wasto describe the effect of Tapinarof cream on the subject-reportedimpression of severity item, global impression of change items, theexpanded POEM, and Daily Sign and Symptom Severity Diary.

Subject Impressions: Subjects provided an overall impression of theirseverity of eczema as well as their impression of change in eczemasymptoms and change in itch.

At Baseline, the majority of subjects in all groups rated their eczemasymptoms as moderate or severe; the vehicle BID group had the highestproportion of subjects with severe eczema symptoms. At Week 12, a higherproportion of subjects in the active treatment groups (>80%) rated theseverity of their eczema symptoms as “very improved” or “moderatelyimproved” compared with subjects in the vehicle groups (<70%).Similarly, at Week 12 in the Tapinarof groups, 78% or more rated theseverity of their itch as “very improved” or “moderately improved”compared with <65% of subjects in the vehicle groups.

Results were similar by age, except for the vehicle BID group, wherebetter ratings were given by the adolescent subjects: 81% were “veryimproved” or “moderately improved” compared with 53% adult subjects foreczema and 64% versus 36%, respectively, for itch.

Expanded Patient-Oriented Eczema Measure (POEM): The expanded POEMincluded 7 items plus 3 additional questions to assess sleep quality.Mean Baseline scores were highest (>3 in all treatment groups;indicating 5 or more days per week) for question #1 (relating to itch)and question #7 (relating to dry or rough skin). For questions #1 to #7,there were mean change reductions (improvements) in all active andvehicle groups through Week 12, except for question #4 for the 1% BIDgroup, with the largest mean change reductions generally found in the0.5% concentration groups. However, this was not consistent for allquestions and time points. Standard deviations were large for alltreatment groups.

In the adult population, there were mean change reductions in all activeand vehicle groups (except question #4) through Week 12 at nearly allvisits, but there were no distinct trends across the treatment groups.For most questions and time points, results in the adolescent populationwere similar to those for the overall population. The mean Baselinescores and the mean change reductions were generally higher in the 0.5%treatment groups than in the other treatment groups in the adolescentpopulation.

An additional 3 questions, not included in the original publishedinstrument, were added to assess sleep quality. For question #8 (howmany nights did you wake up at least once because of the eczema?), themean change reductions were largest in the 0.5% concentration groups(−1.3 and −1.2). For questions #9 (how difficult was it for you to fallasleep because of the eczema?) and #10 (how difficult was it for you tofall back asleep after you had woken up because of the eczema?) thenumber of subjects finding it difficult or very difficult to fall (back)asleep were lower in all treatment groups at Week 12 compared withBaseline, except for 1 subject in the vehicle BID for question #10.There were mean change reductions (improvements) and fewer subjectshaving difficulty falling asleep and falling back asleep because oftheir eczema at Week 12, and in general the largest improvements were inthe active treatment groups.

Daily Sign and Symptom Severity Diary Data: One of the other endpointsassessed was the change from Baseline to Week 12 in the weekly averageDaily Sign and Symptom Severity Diary score of 11 disease-relatedsymptoms as recorded in the subject diary.

The highest mean Baseline scores were seen for dry or rough skin (range:6.2 to 6.9), red or discolored skin (range: 4.8 to 6.0), and flaky skin(range: 4.2 to 5.8). For all items there was a reduction in the meanscore (i.e., improvement) at Week 12 for all treatment groups. However,no clear differences were observed between the treatment groups, exceptthe reduction was consistently smaller for the vehicle BID group for allitems.

Sub-group Efficacy Analysis: Japanese Population

Out of the 247 subjects randomized in this study, 46 subjects wereJapanese. For more details on the demographic and subject baselinecharacteristics of this sub-group.

Investigator Global Assessment (IGA): In the Japanese population, theprimary endpoint analysis, the proportion of subjects who had an IGAscore of clear or almost clear (0 or 1) at Week 12 and a minimum 2-gradeimprovement in IGA score from Baseline to Week 12, showed a numericallyhigher proportion of subjects in the 1% QD group only. The lowestproportion of subjects with treatment success was in the 0.5%concentration groups, with intermediate responses in the 1% BID groupand vehicle groups. With NRI, similar results were obtained, with aclearer separation of both the BID and QD 1% concentration groups fromthe 0.5% and vehicle groups in IGA treatment success. The highestresponder rate was again seen in the 1% QD group. Due to the smallnumber of subjects and large confidence intervals, data should beinterpreted with caution.

The proportion of subjects with IGA treatment success in all activetreatment and vehicle groups tended to increase over time up to Week 12,with a clear separation observed in the GSK2894512 1% QD treatmentgroup. However, due to low subject numbers the trends were notconsistent across treatment groups (e.g., see vehicle QD).

Eczema Area and Severity Index (EASI): A secondary efficacy endpoint,the proportion of subjects with EASI75 from Baseline to each studyvisit, was consistently higher in the 1% BID and 0.5% BID groups thanthe vehicle groups in Japanese subjects. EASI showed a more rapid onsetof action for active groups versus the vehicle groups; the firstresponse in the vehicle groups was only at Week 4. The 1% QD groupshowed the most rapid onset of action and highest response rates at Week1 to Week 4. Due to the small number of subjects and large confidenceintervals, data should be interpreted with caution.

There was a trend for a greater mean percent change reduction in EASIscores from Baseline to each study visit in the active treatment groupsthan in the vehicle groups. The 1% concentration groups showed a greatermean percentage change reduction than the 0.5% concentration groups upto Week 8, inclusive, with the largest reductions in the 1% QD group.

Itch/Pruritus Severity: A secondary objective of the study was to assessthe mean change in weekly itch/pruritus from Baseline to Week 12. In theJapanese population, there was separation between active and vehiclegroups in the mean change reduction in itch/pruritus at Weeks 2 and 4,but not at other time points, although from Week 2 onwards the lowestmean reduction was consistently seen in the vehicle BID group. For theproportion of subjects who achieved a minimum 3-point improvement initch/pruritus, there were no clear trends, but the most consistent bestresponse, with approximately 70% of subjects with a response, was seenin the 1% QD group from Week 4 to Week 12. In the ad-hoc NRI, there wasa clearer separation between active and vehicle groups and again thehighest proportion of responders was seen in the 1% QD group.

Pharmacokinetics: Subjects with atopic dermatitis, BSA involvement >5%and <35%, excluding scalp, and Baseline IGA score of >3 at Baseline,participated in this study in which 2 concentrations of Tapinarof cream(0.5% and 1%) and a vehicle control were evaluated following applicationto all AD lesions (except on the scalp) once or twice daily for 12weeks.

A total of 5 blood samples for PK analysis of Tapinarof were collectedfrom each subject at the following clinic visits: Weeks 1, 2, 4, 8, and12. Subjects were advised to provide PK samples during each of thefollowing 3 time windows: 1 to 3 hours post application, 3 to 6 hourspost application, and 6 to 12 hours post application.

Of the 753 plasma samples obtained from subjects on active treatment,348 plasma samples were quantifiable (lower limit of quantification[LLOQ]=0.04 ng/mL).

Overall, limited Tapinarof PK data are available in AD patients to date.Intensively sampled PK data are only available in AD patients (n=6) fromStudy 201851 Cohort 2 (1% cream BID); hence, the central tendency andvariability in the PK of Tapinarof are not well defined. Given the PKdata limitations, no definitive conclusions on Tapinarof PK from Study203121 can be made at the current time and therefore the data should beinterpreted with caution. Therefore, comparison of PK across relevantsubpopulations (adults, adolescents, Japanese) is not included.

Plasma Concentration Outliers: Elevations in plasma concentrations(>0.84 ng/mL gender averaged NOAEL Cmax of minipig 28 day, formulationF, 3% [60 mg/kg/day]) were observed in 13 out of 247 (5%) subjects. Forall subjects, outlier plasma concentrations were measured at a singletime point and all other plasma concentrations sampled in the samepatient were below the NOAEL. Among these subjects, there was norelationship between the occurrence of high plasma concentration andtiming of AE(s). Reported AEs in these subjects were consistent with thesystem organ class, frequency, and severity of AEs reported across theTapinarof Phase 2 studies. All 13 subjects (5 males, 8 females; agedbetween 12 and 65 years [3 in the adolescent population, 10 in the adultpopulation]), were in the Tapinarof treatment groups. Elevations inplasma concentration were observed in subjects in each of the differenttreatment groups without evidence of a dose effect (2 subjects from the0.5% QD group [2/13, 15%], 4 subjects from the 0.5% BID group [4/13,31%], 2 subjects from the 1% QD group [2/13, 15%], and 5 subjects fromthe 1% BID group [5/13, 38%]. Nine out of the 13 (69%) subjectsexperienced AEs: arthralgia, rash, application site pain, localreaction, diarrhea, dizziness, impetigo, blood creatinine decreased,conjunctivitis, dermatitis atopic, superinfection, application sitereaction, hyperbilirubinemia, nasopharyngitis, sycosis barbae, andfolliculitis. AEs of application site pain and folliculitis wereobserved in more than 1 subject. Overall, the median time to onset(since Day 1) for these events was 41 days with a median duration of 9days. The majority of the events were mild to moderate. Four subjects(4/13, 31%) had AEs (rash, local reaction, application site pain,application site reaction, folliculitis) which were consideredtreatment-related by the investigator. None of the subjects experiencedan SAE. Despite a thorough investigation of relevant patient informationat the study sites, no root cause was identified that could explain theelevated plasma concentrations. The elevated plasma concentrations ofthe aforementioned subjects are presumably spurious. Plasmaconcentrations will continue to be monitored in PK studies.

Subject 110406, a 14-year-old female in the Tapinarof 1% BID groupexperienced mild AEs of arthralgia on Day 1, rash on Day 23, andapplication site pain on Day 38, and local reaction on Day 68. A druginterruption (reason: study drug not tolerated) occurred between Day 29to Day 48 and again from Day 65 to Day 78. PK samples were obtained fromthis subject at Weeks 1, 2, 4, 8, and 12 with concentration values at0.233, 0.347, 4.9, 0.514, and no quantifiable level—below the limit ofquantification (NQ) ng/mL, respectively. The investigator considered theevents of rash, application site pain, and local reaction were relatedto study treatment and the event of arthralgia was unrelated to studytreatment.

Subject 111301, a 12-year-old male in the Tapinarof 0.5% BID groupexperienced severe AEs of dermatitis atopic on Day 65, superinfection onDay 65, and application site reaction on Day 1 and Day 70. PK sampleswere obtained from this subject at Weeks 1, 2, and 4 with concentrationvalues at 6.09, 0.438, and 0.649 ng/mL, respectively. The subject hadwithdrawn treatment on Day 64 and discontinued from the study on Day 69,due to investigator discretion. The Week 1 plasma concentration exceededthe NOAEL Cmax value; however, subsequent plasma samples at Weeks 2 and4 were below the NOAEL. The investigator considered the events ofapplication site reaction were related to study treatment and the eventsof dermatitis and superinfection were unrelated to study treatment.

No other subjects with plasma concentrations above the NOAEL hadtreatment interruptions or withdrew from the study. Plasmaconcentrations and AEs will continue to be monitored in subsequentstudies.

The narratives described below are subjects with plasma concentrationsabove the NOAEL and experienced a systemic AE.

Subject 110604, a 21-year-old female in the Tapinarof 1% BID groupexperienced moderate AEs of diarrhea and dizziness on Day 14, andimpetigo on Day 15. PK samples were obtained from this subject at Weeks1, 2, 4, 8, and 12 with concentration values at 1.48, 0.266, 0.430,0.0716, and 0.311 ng/mL, respectively. The investigator considered theevents were unrelated to study treatment.

Subject 316651, a 27-year-old male in the Tapinarof 1% BID groupexperienced a mild AE of blood creatinine decrease on Day 87. PK sampleswere obtained from this subject at Weeks 1, 2, 4, 8 and 12 withconcentration values at NQ, 181.0, NQ, NQ and NQ ng/mL, respectively.The investigator considered the event was unrelated to study treatment.

Subject 316851, a 20-year-old male in the Tapinarof 0.5% BID groupexperienced a mild AE of hyperbilirubinemia on Day 102. PK samples wereobtained from this subject at Weeks 1, 2, 4, 8 and 12 with concentrationvalues at 0.362, 0.106, NQ, 1.93, and NQ ng/mL, respectively. Theinvestigator considered the event was unrelated to study treatment.

Safety Results

Safety results are reported using the Safety Population. Unlessmentioned otherwise, results reported in this section are those of theoverall population.

Adverse Events: Treatment-emergent adverse events (TEAEs) were reportedin 127 subjects (51%) (the Safety Population comprised 247 subjects).The frequency of TEAEs was higher in the active treatment groups than inthe vehicle groups (93 subjects [56%] vs 34 subjects [41%]).

Overall, TEAEs were considered treatment-related in 32/247 subjects(13%). There was a higher proportion of subjects in the active treatmentgroups than in the vehicle groups with treatment-related TEAEs (24/165[15%] vs 8/82 [10%]). Thirteen of 247 (5%) subjects permanentlydiscontinued treatment due to TEAEs (7/165 [4%] in the active treatmentgroups vs 6/82 [7%] in the vehicle groups). One (<1%) subjectexperienced serious TEAEs (reported from the active treatment group).Most TEAEs were reported as mild (53/165 [32%] in the active treatmentgroups vs 19/82 [23%] in the vehicle groups) or moderate (36/165 [22%]in the active treatment groups vs 12/82 [15%] in the vehicle groups).Seven (3%) subjects overall experienced severe TEAEs (4/165 [2%] in theactive treatment groups vs 3/82 [4%] in the vehicle groups). Notreatment-related serious or fatal TEAEs were reported.

In the adult subjects, TEAEs were considered treatment-related in 22/174subjects (13%); most of these subjects were in the active treatmentgroups compared with vehicle groups (16/116 [14%] vs 6/58 [10%]). Nineof 174 (5%) subjects permanently discontinued treatment due to TEAEs(4/116 [3%] in the active treatment groups vs 5/58 [9%] in the vehiclegroups). No subject experienced serious TEAEs. Most TEAEs were reportedas mild (33/116 [28%] in the active treatment groups vs 13/58 [22%] inthe vehicle groups) or moderate (29/116 [25%] in the active treatmentgroups vs 9/58 [16%] in the vehicle groups). Five (3%) subjects in the18 to 65 years age group experienced severe TEAEs (3/116 [3%] in theactive treatment groups vs 2/58 [3%] in the vehicle groups). Notreatment-related serious or fatal TEAEs were reported.

In the adolescent subjects, TEAEs were considered treatment-related in10/73 subjects (14%); most of these subjects were in the activetreatment groups compared with vehicle groups (8/49 [16%] vs 2/24 [8%]).Four of 73 (5%) subjects permanently discontinued treatment due to TEAEs(3/49 [6%] in the active treatment groups vs 1/24 [4%] in the vehiclegroups). One (1%) subject experienced serious TEAEs (reported from theactive treatment group). Most TEAEs were reported as mild (20/49 [41%]in the active treatment groups vs 6/24 [25%] in the vehicle groups) ormoderate (7/49 [14%] in the active treatment groups vs 3/24 [13%] in thevehicle groups). Two (3%) subjects in the 12 to 17 years age groupexperienced severe TEAEs (1/49 [2%] in the active treatment groups vs1/24 [4%] in the vehicle groups). No treatment-related serious or fatalTEAEs were reported.

In Japanese subjects, TEAEs were considered treatment-related in 5/46subjects (11%); all of these subjects were in the active treatmentgroups (5/30 [17%]). One of 46 (2%) subjects permanently discontinuedtreatment due to TEAEs (1/30 [3%] in the active treatment groups). Nosubject experienced serious TEAEs. Most TEAEs were reported as mild(15/30 [50%] in the active treatment groups vs 5/16 [31%] in the vehiclegroups) or moderate (3/30 [10%] in the active treatment groups vs 2/16[13%] in the vehicle groups). No Japanese subjects experienced severeTEAEs and no treatment-related serious or fatal TEAEs were reported.

The most frequently reported TEAE was nasopharyngitis, which occurred in20/247 subjects (8%) (13/165 [8%] in the active groups vs 7/82 [9%] inthe vehicle groups). Other TEAEs reported in >5% of subjects in any armor in total were: folliculitis, reported in 18 subjects (7%) (18/165[11%] in the active groups vs 0 in the vehicle group), atopic dermatitisin 15 subjects (6%) (6/165, [4%] in the active groups vs 9/82 [11%] inthe vehicle groups), upper respiratory tract infection, reported in 15subjects (6%) (11/165 [7%] in the active groups vs 4/82 [5%] in thevehicle groups), headache, reported in 11 subjects (4%) (9/165 [5%] inthe active groups vs 2/82 [2%] in the vehicle groups), acne, reported in7 subjects (3%) (6/165 [4%] in the active groups vs 1/82 [1%] in thevehicle groups), and impetigo, reported in 4 subjects (2%) (1/165 [1%]in the active groups vs 3/82 [4%] in the vehicle groups). The TEAEs ofatopic dermatitis were reported as AD flare, worsening of AD,aggravation of AD, or increased itching of AD.

In Japanese subjects, nasopharyngitis and folliculitis were also themost frequently reported TEAEs.

Overall, 32 subjects (13%) had TEAEs which were consideredtreatment-related by the investigators. The frequency was higher in theactive treatment groups compared to the vehicle groups (24/165 [15%] inthe active treatment groups vs 8/82 [10%] in the vehicle groups).Folliculitis was the most frequent TEAE which was consideredtreatment-related by the investigators; it was reported in 9 subjects(4%), (9/165 [5%] in the active treatment groups vs 0% in the vehiclegroups). Of these, all subjects with TEAEs which were consideredtreatment-related by the investigator were similarly distributed acrossthe Tapinarof treatment groups, concentration 0.5% or 1% and frequency(BID or QD). Application site pain, was the next most frequent TEAEwhich was considered treatment-related by the investigators; it wasreported in 5 subjects (2%), (2/165 [1%] in the active treatment groupsvs 3/82 [4%] in the vehicle groups). Of these, 1 subject was in theTapinarof 1% group and 1 subject in the 0.5% group, both on a frequencyof BID. In the vehicle arm, 2 subjects were on a frequency of BID and 1subject was on QD.

The following TEAEs which were considered treatment-related by theinvestigators were each reported in 3 subjects (1%) or less: eczemaimpetiginous, herpes simplex, upper respiratory tract infection, atopicdermatitis, acne, contact dermatitis, dermal cyst, dry skin,hyperkeratosis follicularis et parafollicularis, pain of skin, rash,application site reaction, application site erythema, application siteedema, application site pruritus, local reaction, headache, burningsensation, hypoesthesia, diarrhea, nausea, increased hepatic enzyme, anddecreased monocyte count.

In the adult and adolescent populations, the following treatment-relatedTEAEs were reported in both populations: application site pain,application site reaction, acne, atopic dermatitis, folliculitis, andheadache. The incidence of these events was similar in the 2populations, except for application site pain which was more frequentlyreported in adolescent subjects (5% overall) than in adult subjects(1%).

In the Japanese population, TEAEs related to study treatment werereported in the active treatment groups but a dose-response relationshipwas not observed.

Overall, TEAEs led to permanent discontinuation of study treatment in 13subjects (5%). The frequency was higher in the vehicle groups than theactive treatment groups (6/82 [7%] in the vehicle groups vs 7/165 [4%]in the active treatment groups). Atopic dermatitis (reported asworsening or flare of AD—see source Listing 39) was the most frequentTEAE that led to study treatment discontinuation; it was reported in 8subjects (3%), (4/165 [2%] in the active treatment groups vs 4/82 [5%]in the vehicle groups). Of these, all subjects with TEAEs that led tostudy treatment discontinuation in the active treatment arms weretreated with the lower concentrations of cream; 3 subjects (7%) withTapinarof cream 0.5% BID and 1 subject (2%) with Tapinarof cream 0.5%QD.

In Japan, TEAEs led to permanent discontinuation of study treatment in 1subject (2%) in the Tapinarof 0.5% BID group. Subject 317102, a57-year-old female experienced non-serious events of application siteedema, burning sensation, and contact dermatitis. All the events started30 days after the first dose and 1 day after the last dose.

The events occurred on the application site and were considered moderatein intensity. The study treatment was withdrawn and all events resolved14 days after onset. The investigator considered all 3 events to berelated to study treatment.

Serious and Other Significant Adverse Events

Deaths: No deaths were reported during the study.

Other Serious Adverse Events: Serious TEAEs were reported in 1 subject(<1%), who was in the Tapinarof treatment group. Brief summaries ofthese serious TEAEs are provided below.

Anxiety and attention deficit/hyperactivity disorder: A 14-year-old malewith a previous history of anxiety and attention deficit/hyperactivitydisorder was randomized to receive Tapinarof 1% BID. The subject washospitalized due to anxiety and attention deficit/hyperactivity disorder55 days after the first application and 3 days after the lastapplication. Study treatment was withdrawn and events resolved 10 dayslater. The investigator considered the events were unrelated to studytreatment.

Other Significant Adverse Events: No other significant AEs were reportedduring the study. However, a summary of the details of the 5 mostfrequently reported AEs is provided below. The summaries by age showedsimilar results to those seen in the overall population.

Nasopharyngitis: A total of 20 out of 247 (8%) subjects (11 males, 9females; aged between 13 and 49 years) experienced nasopharyngitis, 13of whom (13/20, 65%) were from active treatment groups. The events werereported in 5 subjects from the GSK2894512 1% QD group (5/20, 25%), 4from the 0.5% BID group (4/20, 20%), 3 from the 1% BID group (3/20,15%), 1 from the 0.5% QD group (1/20, 5%), and 7 from the vehicle groups(7/20, 35%). The majority of the events were of mild intensity (18/20,90%) and 2 (2/20, 10%) were considered moderate in intensity. Nosubjects had treatment withdrawn due to the event. All but 2 of thecases were considered recovered or resolved at the time of reporting.The median time to onset (since Day 1) was 43 days (32 days in theactive treatment groups and 52 days in the vehicle groups). The medianduration of the event was 8 days (9 days for the active treatment groupsand 5 days for the vehicle groups). None of the events were consideredrelated to study treatment by the investigators.

In the adult population, 12 subjects (12/174, 7%) experiencednasopharyngitis, 4 (33%) in the 1% QD group, 2 each (17%) in the 1% and0.5% BID groups, and 4 (33%) in the vehicle groups. The median time toonset was 32 days in the active treatment groups with a median durationof 9 days. In the vehicle groups the median time to onset was 73.5 daysand the median duration 4 days.

In the adolescent population, 8 subjects (8/73, 11%) experiencednasopharyngitis: 2 (25%) in the 0.5% BID group, 1 each (12.5%) in the 1%BID, 1% QD and 0.5% QD groups, and 3 (37.5%) in the vehicle groups. Themedian time to onset was 31 days in the active treatment groups and 51days in the vehicle groups, with a median duration of 9 days in bothcases.

Folliculitis: A total of 18 out of 247 (7%) subjects (8 males, 10females; aged between 12 and 49 years), experienced folliculitis, allfrom the active treatment groups. Most of these events were reportedfrom the Tapinarof 1% QD group (8/18, 44%). A majority of the eventswere mild (13/18, 72%) and the rest were considered moderate (5/18,28%). No severe events were reported. No subject had treatment withdrawndue to the event. Most (10/18, 56%) of the events occurred at the studydrug application site. The median start date (since Day 1) offolliculitis was Day 17. The majority of these events wereongoing/resolving (11 ongoing/resolving and 7 resolved) at the end ofthe study follow-up period. Therefore, the AE end dates are not providedin many subjects, indicating that the AE was not resolved at the end ofthe follow-up period in those subjects. Half (9/18, 50%) of the subjectshad events of folliculitis considered related and the other half wereconsidered not related to study treatment by the investigators.

In the adult population, 14 subjects (14/174, 8%) experiencedfolliculitis, all in the active treatment groups: 6 subjects (43%) inthe 1% QD group, 3 (21%) each in the 1% BID and 0.5% QD groups, and 2(14%) in the 0.5% BID. The median time to onset was 17 days.

In the adolescent population, 4 subjects (3/73, 5%) experiencedfolliculitis: 2 (50%) in the 1% QD group, 1 each (25%) in the 1% BID and0.5% BID groups, and none in the vehicle groups. The median time toonset was 23.5 days.

Atopic Dermatitis: A total of 15 out of 247 (6%) subjects (10 males, 5females; aged between 12 and 59 years) experienced a worsening or flareof atopic dermatitis, 6 of whom (6/15, 40%) were from active treatmentgroups. The events were reported in 9 subjects from the vehicle group(9/15, 60%), 2 from the Tapinarof 1% BID group (2/15, 13%), 3 from the0.5% BID group (3/15, 20%), and 1 from the 0.5% QD group (1/15, 7%). Amajority of the events were of moderate intensity (9/15, 60%), 2/15(13%) were considered mild, and 4/15 (27%) were considered severe. Eightsubjects (8/15, 53%) had treatment withdrawn and 3 subjects (3/15, 20%)had treatment interrupted due to the event. Six subjects (6/15, 40%) hadongoing events at the time of reporting and the rest wereresolving/resolved. Seven subjects (7/15, 47%) had events which occurredat the study drug application site. The median time to onset (sinceDay 1) was 21 days (40.5 days in the active treatment groups and 12 daysin the vehicle groups). The median duration of the event was 8.5 days(12.5 days for the active treatment groups and 8 days for the vehiclegroups). Three subjects (3/15, 20%) had events which were consideredrelated to study treatment by the investigators.

In the adult population, 12 subjects (12/174, 7%) experienced atopicdermatitis, 2 (17%) in the 1% BID group, 1 each (8%) in the 0.5% BID andQD groups, and 4 each (33%) in the vehicle BID and QD groups. The mediantime to onset was 40.5 days in the active treatment groups with a medianduration of 22.5 days. In the vehicle groups the median time to onsetwas 9 days and the median duration 8 days.

In the adolescent population, 3 subjects (3/73, 4%) experienced atopicdermatitis: 2 (67%) in the 0.5% BID group and 1 (33%) in the vehicle QDgroup. The median time to onset was 34 days in the active treatmentgroup with a median duration of 6.5 days, the event in the vehicle groupstarted 68 days after Day 1 and lasted 17 days.

Upper Respiratory Tract Infection: A total of 15 out of 247 (6%)subjects (10 males, 5 females; aged between 14 and 59 years) experiencedupper respiratory tract infection, 11 of whom (11/15, 73%) were fromactive treatment groups. The events were reported in 4 subjects from theTapinarof 1% BID group (4/15, 27%), 2 from the 1% QD group (2/15, 13%),3 from the 0.5% BID group (3/15, 20%), and 2 from the 0.5% QD group(2/15, 13%). The majority of the events were of mild intensity (10/15,67%) and the rest (5/15, 33%) were considered moderate. No subjects hadtreatment withdrawn due to the event. Two events were ongoing and therest were considered resolved at the time of reporting. The median timeto onset (since Day 1) was 32.5 days (32.5 days in the active treatmentgroups and 29.5 days in the vehicle groups). The median duration of theevent was 11.5 days (16.5 days for the active treatment groups and 10.5days for the vehicle groups). Only 1 of these events was consideredrelated to study treatment by the investigator.

In the adult population, 13 subjects (13/174, 7%) experienced upperrespiratory tract infection, 4 (31%) in the 1% BID group, 3 (23%) in the0.5% BID group, 2 (15%) in the 1% QD group, 1 (8%) in the 0.5% QD group,and 3 (23%) in the vehicle groups. The median time to onset was 38 daysin the active treatment groups with a median duration of 22 days. In thevehicle groups the median time to onset was 9 days and the medianduration 9 days.

In the adolescent population, 2 subjects (2/73, 3%) experienced upperrespiratory tract infection, 1 (50%) in the 0.5% QD group and 1 (50%) inthe vehicle BID group. The time to onset was 8 days in the activetreatment group with a duration of 6 days, the event in the vehiclegroup started 50 days after Day 1 and lasted 12 days.

Headache: A total of 11 out of 247 (4%) subjects (6 males, 5 females;aged between 14 and 41 years) experienced headache, 9/11 (82%) fromactive treatment groups and 2/11 (18%) from vehicle groups. The mostevents of headache were reported in subjects in the Tapinarof 1% BIDgroup (4/11 [36%]). The majority of subjects had events (8/11, 73%) thatwere of mild intensity and the rest (3/11, 27%) were considered moderatein intensity. One subject (1/11, 9%) had treatment withdrawn due to theevent. All, except 1 event, were considered resolved at the time ofreporting. The median time to onset (since Day 1) was 3 days (2 days inthe active treatment groups and 52 days in the vehicle groups). Themedian duration of the event was 1.5 days (2 days for the activetreatment groups and 1 day for the vehicle groups). Three of the eventswere considered related to study treatment by the investigators.

In the adult population, 9 subjects (9/174, 5%) experienced headache: 3(33%) in the 1% BID group, 2 (22%) subjects in the 0.5% QD group, and 1each (11%) in the 1% QD and the 0.5% BID groups, and 2 (22%) in thevehicle QD group. The median time to onset was 3 days in the activetreatment groups with a median duration of 2 days. In the vehicle groupthe median time to onset was 52 days and the median duration 1 day.

In the adolescent population, 2 subjects (2/73, 2%) experiencedheadache: 1 each (50%) in the 1% BID and 0.5% QD groups, and none in thevehicle groups. The median time to onset was 1 day in the activetreatment groups with a median duration of 2 days.

Clinical Laboratory Evaluations: Elevations in liver chemistries(ALT/aspartate aminotransferase [AST]>2×ULN) were seen in 6 subjects,all in Tapinarof treatment groups. The elevations did not triggerprotocol-mandated liver stopping criteria, the subjects all continuedtreatment, and all elevations resolved. Plasma concentrations for thesesubjects were reviewed to determine if any relationship with systemicexposure and/or timing of liver chemistry elevations existed; norelationships were observed.

Seven subjects had laboratory-related AEs which are presented below:

Subject 317101, a 12-year-old male, in the Tapinarof 0.5% BID group hada mild non-serious AE of decreased monocyte count (0.07 G/L). The eventstarted 97 days after the first application and 15 days after the lastapplication, during the follow-up period. The event of decreasedmonocyte count was ongoing at the time of reporting. The investigatorconsidered the event was related to study treatment.

Subject 316651, a 27-year-old male, in the Tapinarof 1% BID group had amild non-serious AE of blood creatinine decreased (63.6 μmol/L). Theevent started 87 days after the first application and 3 days after themost recent application. The study drug dose was not changed and theevent resolved 15 days after onset (value of 70.7 μmol/L). Theinvestigator considered the event was unrelated to study treatment.

Subject 316652, a 22-year-old male, in the vehicle BID group had a mildnon-serious AE of blood creatinine decreased (61.9 μmol/L). The eventstarted 29 days after the first application and 2 days after the mostrecent application. The study drug dose was not changed and the eventresolved 75 days after onset (value of 69 μmol/L). The investigatorconsidered the event was unrelated to study treatment.

Subject 316851, a 20-year-old male, in the Tapinarof 0.5% BID group hada mild non-serious AE of hyperbilirubinemia (42 μmol/L). The eventstarted 102 days after the first application and 18 days after the lastapplication. The event was ongoing at the time of reporting. Theinvestigator considered the event was unrelated to study treatment.

Subject 110360, a 19-year-old female, in the Tapinarof 1% BID group hada moderate non-serious AE of alanine aminotransferase increased (183IU/L). Her AST value was also >6×ULN (590 IU/L) at the time of theevent. The event started 58 days after the first application. The studydrug dose was not changed and the event resolved 11 days after onset(ALT 18 IU/L and AST 23 IU/L). The investigator considered the event wasunrelated to study treatment.

Subject 110202, a 41-year-old female, in the Tapinarof 0.5% QD group hada mild non-serious AE of transaminases increased (ALT 91 IU/L, AST 44IU/L). The event started 15 days after the first application and 1 dayafter the most recent application. The study drug dose was not changedand the event resolved 14 days after onset (ALT 16 IU/L, AST 15 IU/L).The investigator considered the event was unrelated to study treatment.

Subject 111103, a 19-year-old male, in the Tapinarof 0.5% BID group hada mild non-serious AE of increased hepatic enzyme (ALT 89 IU/L, AST 75IU/L). The event started 16 days after the first application and 1 dayafter the most recent application. The study drug dose was not changeddue to this event and the event resolved 28 days after onset (ALT 17IU/L, AST 30 IU/L). The investigator considered the event was related tostudy treatment.

Other Safety Evaluations: Overall, there were no clinically significantchanges in vital signs during the study. Overall, 10 subjects (4%) hadsystolic blood pressure readings, 6 subjects (2%) had diastolic bloodpressure readings, and 3 subjects (1%) had pulse rates which were ofpotential clinical importance, but no corresponding related AEs werereported.

A total of 49 subjects (20%) had abnormal clinically significant ECGs atany post-screening visit during the study. Of these, more subjects werein the 1% treatment groups (12 subjects [30%] were in the Tapinarof 1%BID group and 10 subjects [24%] in the Tapinarof 1% QD), compared to 5subjects (12%) in the Tapinarof 0.5% BID group and 8 subjects (21%) inthe Tapinarof 0.5% QD group. However, the incidences in the vehiclegroups were also similar to the active groups (5 subjects [12%] in thevehicle BID group and 9 subjects [23%] in the vehicle QD group).

Tolerability Evaluations by Subjects and Investigators: One of thesecondary objectives of the study was to describe the tolerability ofTapinarof cream as assessed by the investigator and subject measuringlocal (application site) tolerability scores over time as a secondaryendpoint.

No difference in subject-reported tolerability scores was apparentbetween the 2 Tapinarof cream concentrations (0.5% and 1%) or betweenthe 2 frequencies of application (QD or BID) tested. Tolerability scoresimproved during the course of the study. The proportion of subjects withthe best tolerability score (score 0 or “none”) increased from Week 1 toWeek 12 across all study treatment groups.

In total, investigators assessed most subjects (>70%) as having thelowest irritation score (0 or “no irritation”) from Week 1 onwards. Bytreatment group, the lowest proportion of subjects with “no irritation”tended to be seen in the 1% BID group and the vehicle QD group.

Pregnancies: No pregnancies were reported during the study.

Immunoglobulins and Immunophenotyping: No clinically-significant changeswere observed for either the adult or the adolescent populations inimmunoglobulins (IgA, IgG, and IgM) across all treatment groupsreceiving either Tapinarof or vehicle and regardless of dosingfrequency.

No clinically-significant changes were observed for either the adult orthe adolescent populations in immunophenotyping across all treatmentgroups receiving either Tapinarof or vehicle regardless of dosingfrequency.

Health Outcomes

One of the objectives of this study was to describe the effect ofTapinarof cream on subject-reported outcomes, for which subjectscompleted a Subject Impression of Severity and Change questionnaire, theexpanded POEM, and the Daily Sign and Symptom Severity Diary (includingthe NRS itch/pruritus item).

Discussion and Conclusions

Discussion

The objective of this randomized, double-blind, vehicle controlled PhaseII study was to evaluate the efficacy and safety of two doses ofTapinarof/GSK4985212 cream (0.5% or 1%) applied either QD or BID inadolescent and adult subjects with AD over a 12-week treatment period.The characterization of population PK of Tapinarof cream after topicalapplication was also an objective of the study.

Study population: The population enrolled in this study was consistentwith a moderate to severe AD patient population. Specifically, subjectshad a mean Baseline IGA score of 3.1 and 3.0 in the overall and theJapanese populations, respectively. Demographic and Baselinecharacteristics were generally similar across treatment groups.Withdrawal rates were higher in the 2 vehicle groups (>30%) than the 4active treatment groups (12% to 28%).

Efficacy Discussion

Overall: Treatment success rates at Week 12 were: 53% [1% BID]; 46% [1%QD]; 37% [0.5% BID]; 59 34% [0.5% QD]; 24% [vehicle BID]; 28% [vehicleQD]. The rate (53%) of 1% BID was statistically significantly higherthan (24%) vehicle BID. Treatment success was maintained for 4 weeksafter end of tapinarof treatment. Treatment-emergent adverse events(TEAE) were higher with tapinarof (93/165; 56%) vs. vehicle (34/82; 41%)and mild-to-moderate in intensity.

The primary analysis showed a separation between 3 of the activetreatment groups (1% BID, 1% QD, and 0.5% BID) and the vehicle groupswith regards to the primary endpoint (proportion of subjects whoachieved an IGA score of 0 or 1 at Week 12 and a minimum 2-gradeimprovement in IGA score from Baseline to Week 12). FIG. 1 demonstratesTapinarof 1% showed statistical significance over vehicle after 4 weeksof treatment at multiple time points. Generally, an increase in IGAtreatment success could be seen in all groups by Week 2, with separationof active from vehicle at Week 4. The proportion of subjects with IGAtreatment success then tended to increase in magnitude up to Week 12,with the 1% concentration groups having a higher proportion ofresponders at each time point compared to the 0.5% concentration groups.The only exception to this was in the QD active groups, where theproportion improved to Week 8 and then decreased slightly at Week 12.After the end of treatment the proportion of subjects with IGA treatmentsuccess started to decrease again in all groups.

The secondary endpoint of the proportion of subjects with EASI75 fromBaseline to each study visit was higher in all 4 active treatment groupsthan in the vehicle groups from Week 2, with the clearest differenceseen with the same 3 active treatment groups (1% BID, 1% QD, and 0.5%BID) as was seen for the primary endpoint. The maintenance of responsein the 4 weeks after the end of treatment was also improved in the BIDgroups compared with vehicle.

Mean percent change reduction in EASI scores from Baseline to each studyvisit was higher in active treatment groups than in vehicle groupsthroughout the treatment period. Similar improvement over time wasobserved for the mean percent change reduction in EASI scores for both1% concentration groups (BID and QD), leading to the conclusion that theQD application had similar efficacy level to BID and would provide lowerexposure than BID; therefore, it should be chosen for future Phase IIIstudies. Also, the QD application offers an ease of use advantage thatcould lead to future subject treatment adherence.

FIG. 2 provides photographs which demonstrate improvement in IGA andEASI at Weeks 8 and 12. FIG. 3 provides a graphical depiction of theproportion of patients with greater than or equal to 75% improvement inEASI (EASI75) from baseline (EASI75) at each study visit usingnon-responder imputation.

The frequency of application of Tapinarof, QD or BID, had no cleareffect on the primary or main secondary endpoints.

Generally the adult population demonstrated a pattern consistent to thatof the overall population with regard to efficacy endpoints: the primaryendpoint analysis showed a higher proportion of subjects responded inthe active treatment groups than the vehicle groups. For EASI75 and meanreduction in % BSA the response patterns were also consistent. In theadolescent population, patterns differed somewhat, with strongerresponses seen in the vehicle BID group compared with the otherpopulations across the efficacy endpoints, but due to the smaller samplesize of this population, the data should be interpreted with caution.

To adjust for the higher dropout rates in the vehicle group, theefficacy data were reanalyzed after unblinding using NRI method.Overall, with this method, the aforementioned efficacy results wereunaltered, confirming the robustness of the data. In addition, theefficacy results showed a clear separation between each of the doses ofthe active treatment and the vehicle groups with each the active groupsshowing a higher response rate than the vehicle groups at Week 12.

Results from other clinical evaluations assessed from Baseline to eachstudy visit such as mean change reduction in % BSA affected and TSS, andreduction in itch/pruritus symptoms were also supportive of thetherapeutic effect of Tapinarof cream, as compared to vehicle. FIG. 4graphically depicts the patients who achieved a minimum 3-pointimprovement in weekly average of Itch/Pruritus NRS from baseline at eachstudy visit—non-responder imputation (ITT Population). However, datafrom the POEM and the Daily Sign and Symptom Severity Diary did notfollow this pattern: there were no consistent differences observedbetween active treatment groups and vehicle groups, although the meanreductions (improvements) were consistently smaller for the vehicle BIDgroup compared with the other treatment groups for the Daily Sign andSymptom Severity Diary. Also, for the assessment of sleep quality in theexpanded POEM, the largest improvements at Week 12 were generally in theactive treatment groups.

Subjects' impressions of the severity of their eczema symptoms fromBaseline to Week 12, as well as investigators' assessments, correspondedwith the clinical evaluations. Most subjects rated the change in theseverity of their eczema symptoms, as well as the change in the severityof their itch, as “very improved” or “moderately improved” by the end of12 weeks of treatment with Tapinarof cream.

Subject impressions: At baseline, 86% of subjects rated their ADsymptoms as moderate or severe across all treatment groups: 28-60% ratedas moderate and 28-53% rated as severe. At Week 12, 64% (1% BID), 59%(1% QD), 47% (0.5% BID) and 40% (0.5% QD) of subjects in the tapinarofcream groups reported the severity of their AD symptoms as ‘veryimproved’ vs 21% (BID) and 28% (QD) in the vehicle groups (FIG. 5 a ).At Week 12, the majority of subjects treated with tapinarof cream(78-87% in the 1% groups and 80-81% in the 0.5% groups) rated theseverity of their pruritus symptoms as ‘very improved’ or ‘moderatelyimproved’ compared with the vehicle groups (47-64%) (FIG. 5 b ).

Expanded POEM: At Week 12, improvements were observed in all tapinarofcream and vehicle treated groups on all seven POEM items, except for thequestion relating to weeping or oozing for the 1% BID group. The threeadditional items in the expanded POEM showed overall sleep qualityimproved across all treatment groups, with the largest improvements inthe tapinarof cream groups. For item 8 related to how many nights didsubjects wake up at least once because of AD, the mean change reductionswere largest in the tapinarof cream 0.5% groups (BID: −1.3 and QD:−1.2). For items 9 and 10 related to how difficult it was it forsubjects to fall asleep or fall back asleep after waking because of AD,the number of subjects finding it difficult or very difficult to fall(back) asleep were lower in all treatment groups at Week 12 comparedwith baseline, except for one subject in the vehicle BID group for item10.

Daily Sign and Symptom Severity Diary: The highest mean baseline scoreswere seen for dry or rough, red or discolored, and flaky skin. Overallthere was an improvement in dry or rough, red or discolored, and flakyskin in all treatment groups as measured by the Daily Sign and SymptomSeverity Diary scores, with the improvement being consistently smallerfor the vehicle BID group vs the active tapinarof treatment groups forall items.

In the Japanese population, subject numbers were low, and there was astrong response in the vehicle BID group, so trends were not so clear.

Limited Tapinarof PK data are available in AD patients to date.Intensively sampled PK data are available in AD patients (n=6) fromStudy 201851; hence, the central tendency and variability in the PK ofTapinarof are not well defined. Given the PK data limitations, nodefinitive conclusions on the plasma PK of Tapinarof from Study 203121can be made at the current time and therefore the data should beinterpreted with caution. Therefore, comparison of PK across relevantsubpopulations (adults, adolescents, Japanese) is not included.

Safety Discussion

The frequency of TEAEs was higher in the active treatment groups than inthe vehicle groups (56% and 41%, respectively) and more TEAEs wereconsidered treatment related in the active treatment groups (15%) thanin the vehicle groups (10%). Most TEAEs were mild or moderate, with 2%and 4% (in active treatment and vehicle groups, respectively) beingreported as severe. The frequency of TEAEs leading to permanentdiscontinuation of study treatment was higher in the pooled vehiclegroups than the pooled active treatment groups (7% vs 4%), with the mostcommon AE leading to discontinuation being worsening or flare of atopicdermatitis, which was reported in the 0.5% treatment groups and vehiclegroups only; this may indicate a lack of efficacy compared with the 1%treatment groups. One subject in the 1% BID active treatment groupexperienced SAEs of anxiety and attention deficit/hyperactivity disorderthat were considered unrelated to study treatment. No deaths and noother significant AEs were reported during the study.

The 1% QD treatment may have a slightly better safety profile than the1% BID treatment, based on a lower frequency of TEAEs (54% versus 70%).

Overall, the most commonly reported TEAEs (>5% in any arm or in total,regardless of relationship to study treatment) were nasopharyngitis(8%), folliculitis (7%), atopic dermatitis (6%), upper respiratory tractinfection (6%), headache (4%), acne (3%), and impetigo (2%). Comparingactive with vehicle, the most commonly reported TEAEs (>5% in eitherpooled arm) were folliculitis (11% in the active groups versus 0% in thevehicle groups), nasopharyngitis (8% versus 9%), upper respiratory tractinfection (7% versus 5%), headache (5% versus 2%), and atopic dermatitis(4% versus 11%). The most common treatment-related TEAEs (>5% in anyarm) were folliculitis (5% and 0% in active treatment and vehiclegroups, respectively) followed by application site pain (1% and 4%,respectively), and atopic dermatitis (1% and 2%, respectively). Allother treatment-related TEAEs were reported in <1% of subjects overall:eczema impetiginous, herpes simplex, upper respiratory tract infection,atopic dermatitis, acne, contact dermatitis, dermal cyst, dry skin,hyperkeratosis follicularis et parafollicularis, pain of skin, rash,application site reaction, application site erythema, application siteedema, application site pruritus, local reaction, headache, burningsensation, hypoesthesia, diarrhea, nausea, increased hepatic enzyme, anddecreased monocyte count. No treatment-related TEAEs were assessed asserious.

The incidence and type of AEs in the adult and adolescent populationswere consistent with that seen in the overall population: in all 3populations the overall frequency of TEAEs was just over 50%,drug-related TEAEs were just under 15%, and TEAEs leading to permanentdiscontinuation of study treatment were 5%. In the adolescentpopulation, compared with the adult population, there was a lowerincidence of TEAEs of moderate intensity in the active treatment groups(14% in the adolescent population versus 25% in the adult population);the incidence in the vehicle groups was similar (13% and 16%,respectively).

The topical tolerability of Tapinarof cream, as judged by subjects aswell as investigators, was very similar compared with vehicle and acrossconcentration groups (0.5% and 1%) and with both frequencies ofapplication (QD or BID). Tolerability improved from Week 1 to Week 12.

Elevations in liver chemistries (ALT/AST >2×ULN) were seen in 6subjects, all in Tapinarof treatment groups. The elevations did nottrigger protocol-mandated liver stopping criteria, the subjects allcontinued treatment, and all elevations resolved. No other clinicallysignificant changes in laboratory values were reported.

Safety: Overall, 51% (127/247) of subjects had treatment-emergent AEs(TEAEs): 56% in the tapinarof cream groups and 41% in the vehicle groups(Table 4), and were mostly mild to moderate in severity. The mostfrequently reported TEAE was nasopharyngitis, which occurred in 20 (8%)subjects (8% in the tapinarof cream groups and 9% in the vehiclegroups).

TABLE 4 Safety overview and most common TEAEs occurring in ≥ 5% ofsubjects in any group Tapinarof 1% Tapinarof 0.5% Vehicle Preferredterm, BID QD BID QD BID QD n (%) (n = 40) (n = 41) (n = 43) (n = 41) (n= 42) (n = 40) Any TEAE 28 (70) 22 (54) 20 (47) 23 (56) 19 (45) 15 (38)Treatment-  6 (15)  6 (15)  8 (19)  4 (10)  6 (14) 2 (5) related TEAEsSerious TEAEs 1 (3) 0   0   0   0   0   Discontinuous 1 (3) 0    5 (12)1 (2)  4 (10) 2 (5) due to TEAEs TEAEs occurring in ≥ 5% of subjects inany group Nasopharyngitis 3 (8)  5 (12) 4 (9) 1 (2)  4 (10) 3 (8)Folliculitis  4 (10)  8 (20) 3 (7) 3 (7) 0   0   Dermatitis 2 (5) 0   3(7) 1 (2)  4 (10)  5 (13) atopic URTI  4 (10) 2 (5) 3 (7) 2 (5) 3 (7) 1(3) Headache  4 (10) 1 (2) 1 (2) 3 (7) 0   2 (5) Acne 2 (5) 0   1 (2) 3(7) 1 (2) 0   Impetigo 1 (3) 0   0   0   0   3 (8)

Overall, Tapinarof cream showed an acceptable safety and tolerabilityprofile.

Conclusions

The proportion of subjects who achieved an IGA score of clear or almostclear (0 or 1) at Week 12 and a minimum 2-grade improvement in IGA scorefrom Baseline to Week 12 was higher in 3 of the active treatment groups(1% BID or 1% QD, or 0.5% BID) than in vehicle groups.

IGA treatment success in active treatment groups were observed from Week1, separated from vehicle at Week 4, peaked at Week 8 or Week 12 andstarted to decrease after the end of treatment.

The frequency of application (BID or QD) had no clear effect on the IGAtreatment success over time.

The proportion of subjects with EASI75 from Baseline to Week 12 wasclearly higher in all active treatment groups than in vehicle groups.

In general, in the active groups, EASI75 appeared from Week 2, peaked atWeek 12 and was durable, lasting up to 4 weeks after the end oftreatment, particularly in the 0.5% BID group.

Mean percent change reduction in EASI scores from Baseline to each studyvisit was higher in all active treatment groups than in vehicle groupsthroughout the treatment period.

The frequency of application (QD or BID) had little effect on the meanpercent change reduction in EASI scores, and indicates that the QDapplication has similar efficacy level to BID and would provide lowerexposure than BID; therefore, it should be chosen for future Phase IIIstudies. Also, the QD application offers an ease of use advantage thatcould lead to future subject treatment adherence.

Evaluation of mean change reduction in % BSA affected and TSS, andreduction in itch/pruritus symptoms were also supportive of thetherapeutic effect of Tapinarof cream, as compared to vehicle.

Generally the adult population demonstrated a pattern consistent to thatof the overall population with regard to the main efficacy endpoints. Inthe adolescent population, patterns differed somewhat, with strongerresponses seen in the vehicle BID group across the efficacy endpoints,but the sample size was small.

Subject, as well as investigator, impressions of the severity of ADsymptoms corresponded with clinical evaluations. Most subjects rated thechange in the severity of their eczema symptoms as “very improved” or“moderately improved” by the end of treatment with Tapinarof cream (Week12).

Given the limited available data, Tapinarof population PK was notcharacterized.

Tapinarof cream showed an acceptable safety profile. There were notreatment-related serious TEAEs reported. The most frequenttreatment-related TEAEs (>5% in any arm) were folliculitis, followed byapplication site pain, and atopic dermatitis.

The incidence and type of AEs in the adult and adolescent populationswere generally consistent with that seen in the overall population;there was a lower incidence of moderate AEs in the adolescent populationthan in the overall and adult populations.

Elevations in liver enzymes were seen in 6 subjects in the activetreatment groups, however the elevations did not triggerprotocol-mandated liver stopping criteria, the subjects continuedtreatment, and all elevations resolved. No other clinically significantchanges in laboratory values were reported.

The topical tolerability of Tapinarof cream, as judged by subjects aswell as investigators, was similar across concentration groups (0.5% and1%) and with both frequencies of application (QD or BID). Tolerabilityimproved from Week 1 to Week 12.

Based on the lower incidence of TEAEs, the 1% QD treatment may have aslightly better safety profile than the 1% BID treatment.

Additional Analysis.

Primary endpoint—efficacy based on percentage of patients who achievedminimum two-point improvement in IGA score and assessment of “clear” or“almost clear” skin, referred to as “treatment success.”

Secondary endpoint—EASI score, BSAA score, itch improvement, change intotal severity score, subject impressions of symptom severity and safetyand tolerability.

Using a post-hoc analysis to account for missing data due to the highrate of dropout in the vehicle group, at week 12, 53% of patientstreated with 1% BID (statistically significant compared to vehicle) and46% treated with 1% QD met treatment success, compared with 24% and 28%for vehicle BID and QD, respectively. At week 12, 37% of patientstreated with 0.5% BID and 34% treated with 0.5% QD met treatmentsuccess.

At week 12, 60% and 51% of patients achieved a 75% improvement in EASIscore in 1% BID and 1% QD groups, respectively (statisticallysignificant compared to vehicle). Statistical significance was achieved,and the endpoint was met, for all tapinarof groups compared to vehicle,with the exception of 0.5% QD.

At week 12, subjects treated with both 0.5% and 1% concentrations showedgreater improvements in mean change in percentage BSA affected frombaseline (as demonstrated by an absolute change in percent BSA affectedof 11.2 for 1% BID and 11.6 for 1% QD, respectively, compared with 6.0for BID vehicle and 5.4 for QD vehicle). While statistical significancewas not evaluated for this endpoint, the endpoint was determined to bemet.

At week 12, subjects treated with both 0.5% and 1% concentrations showedgreater improvements in mean change in total severity score (reductionof 5.8 for 1% BID and 5.5 for 1% QD, compared with 4.6 for BID vehicleand 5.2 for QD vehicle). Statistical significance was not evaluated forthis endpoint and we could not determine that the endpoint was met.

At week 12, subjects treated with both 0.5% and 1% concentrations showedgreater improvements in subject impressions of symptom severity (64% for1% BID and 59% for 1% QD categorized symptoms as very improved, comparedwith 21% for BID vehicle and 28% for QD vehicle). While statisticalsignificance was not evaluated for this endpoint, the endpoint wasdetermined to be met. In particular, at week 12, based on subjectimpressions of change in severity of pruritus, most patients treatedwith tapinarof 1% (78% BID and 86% QD) rated their itch to be“moderately improved” to “very improved” compared to patients treatedwith vehicle (46% BID and 64% QD). While statistical significance wasnot evaluated for this endpoint, the endpoint was determined to be met.

At week 12, 30% and 33% of patients treated with tapinarof 1% BID and0.5% BID, respectively, achieved a minimum three-point improvement initch numerical rating score, or NRS, compared to 5% treated with vehicleBID. Similarly, at week 12, 32% and 29% of patients treated withtapinarof 1% QD and 0.5% QD, respectively, achieved a minimumthree-point improvement in itch NRS, compared to 15% treated withvehicle QD. While statistical significance was not evaluated for thisendpoint, the endpoint was determined to be met.

Generally well tolerated at 0.5% and 1% concentrations, with majority ofAEs and treatment emergent AEs reported as mild or moderate. 133subjects experienced at least one AE (97 in treatment groups). 127subjects experienced at least one treatment-emergent adverse event, orTEAE (93 in treatment groups). A TEAE is defined as an AE which occurredon or after the start date of study treatment and on or before the lastvisit.

32 subjects had TEAEs that were considered related to treatment (24subjects in the treatment groups). The most common treatment-relatedTEAEs were folliculitis, application-site pain, and atopic dermatitisupper respiratory tract infection and headache. One subject reported aserious TEAE, which was not considered related to treatment. 13 subjectsdiscontinued prior to end of treatment period due to TEAEs.

Example 2—Results of Phase II Clinical Study in Psoriasis

The present study, which included 227 subjects, was conducted toevaluate the efficacy and safety of a range of concentrations ofTapinarof cream for the topical treatment of psoriasis. Results of thisstudy will be used to select the most appropriate concentration andapplication frequency of Tapinarof cream to evaluate in confirmatoryPhase III clinical studies.

The study objectives and the associated endpoints were as described inTable 5.

TABLE 5 Study Objectives and Associated Endpoints Objectives EndpointsPrimary To estimate the relationship Proportion of subjects who had abetween Tapinarof cream PGA score of clear or almost clear (0concentrations (0.5% and 1%) or 1) at Week 12 and a minimum 2- andapplication frequency with grade improvement in PGA score efficacyresponse, based upon from Baseline to Week 12 clinical evaluations insubjects with plaque psoriasis Secondary To estimate the efficacy ofProportion of subjects with ≥75% Tapinarof cream improvement in PASIfrom Baseline to each study visit Proportion of subjects with a minimum2-grade improvement in PGA score from Baseline to each study visitProportion of subjects with a PGA score of 0 or 1 at each study visitMean change in % BSA affected from Baseline to each study visit Meanchange in PASI score from Baseline to each study visit PGA scores ateach study visit Mean change in PGA score from Baseline to each studyvisit Mean change in individual target lesion grading scores (erythema,scaling, and induration) from Baseline to each study visit Mean changein itch/pruritus NRS from Baseline to each study visit Proportion ofsubjects who achieved a PGA score of 0 or 1 and a minimum 2-gradeimprovement from Baseline to each study visit To describe the safety andIncidence, frequency, and nature of tolerability of Tapinarof cream AEsand SAEs Local tolerability scores over time Change over time inclinical laboratory tests and frequency of clinically-significantabnormal test results Change over time in vital signs and frequency ofclinically-significant abnormal results Incidence and nature of abnormalECGs Other To describe the effect of Change over time in daily PSDTapinarof cream on subject- Subject impression of change in reportedoutcomes psoriasis symptom severity from Baseline to Week 12 Tocharacterize the population Population estimates of PK pharmacokinetics(PK) of parameters, as data permit Tapinarof after topical applicationof Tapinarof cream To explore the relationship Relationship betweencream between topical application (as concentration and/or % BSA treatedcream concentration and % BSA and changes in systemic exposure astreated), efficacy, and/or safety, data permit and systemic exposure ofRelationship between systemic Tapinarof, as data permit exposure andchanges in efficacy (e.g., PGA score) and/or safety endpoints, asappropriate To estimate the duration of Proportions of subjects whoachieved response of Tapinarof cream a PGA score of 0 or 1 and a minimum2-grade improvement from Baseline at Week 12 and maintained theimprovement at 2 and 4 weeks post-treatment Proportions of subjects whoachieved improvement with respect to individual secondary efficacyendpoints at Week 12 and maintained the improvement at 2 and BSA, BodySurface Area; ECG, electrocardiogram; NRS, numeric rating scale; PASI,Psoriasis Area and Severity Index; PGA, Physician Global Assessment;PSD, Psoriasis Symptom Diary; SAE, serious adverse event. 4 weeks post-treatment, as appropriate

Study Design

This was a multicenter (United States, Canada, and Japan), randomized,double-blind (Sponsor-unblind), vehicle-controlled, 6-arm,parallel-group, dose-finding study in adult subjects with psoriasis.Certain study personnel at each site were unblinded to dose-frequency.

The study consisted of 3 periods: up to 4 weeks Screening, 12 weeksdouble-blind treatment, and 4 weeks post-treatment follow-up. Studyvisits occurred at Screening; Baseline; weeks 1, 2, 4, 8, and 12 duringthe treatment period; and 2 and 4 weeks after the last application ofstudy treatment (i.e., at weeks 14 and 16). Additional visits couldoccur, as needed, for early withdrawals or to follow-up on any skinreactions or ongoing AEs. A subject's total duration of studyparticipation was approximately 16 to 20 weeks.

Two concentrations of Tapinarof cream (0.5% and 1%) and a vehiclecontrol were evaluated following application to all psoriasis lesions(except on the scalp) once (QD) or twice daily (BID) for 12 weeks. Therewere no planned dose adjustments during the study.

It was expected that approximately 270 adult subjects would be screenedto achieve 228 randomized subjects (1:1:1:1:1:1; N=38 for each of the 6treatment groups; vehicle once daily:vehicle twice daily:0.5% oncedaily:0.5% twice daily:1% once daily:1% twice daily) and approximately204 evaluable subjects overall. Approximately 30 subjects were to berandomized in Japan to achieve at least 24 evaluable Japanese subjects.

The intent-to-treat (ITT) Population included all randomized subjects.Subjects that prematurely discontinued from the study were not replaced.

Efficacy was assessed by using a 5-point static Physician GlobalAssessment (PGA) (0-4 scale), the Psoriasis Area and Severity Index(PASI), % BSA involvement, target lesion assessments (erythema, scaling,and plaque thickness), and subject-reported itch/pruritus severity usinga numeric rating scale (NRS) (from the Psoriasis Symptom Diary [PSD]).Additional subject-reported outcomes included the daily PSD (which alsocontained severity and bother items for 3 additional symptoms).Investigator global impression of change item (assessing change inseverity of psoriasis symptoms) and 2 subject global impressions ofchange items (assessing change in severity of psoriasis symptoms andchange in severity of itch/pruritus) were also assessed.

Safety was assessed by the monitoring and recording of all AEs andserious adverse events (SAEs); evaluation of local (application site)tolerability; monitoring of hematology (including peripheral bloodImmunophenotyping and Immunoglobulins), clinical chemistry, and vitalsigns; and the performance of ECGs and physical examinations.

An Independent Data Monitoring Committee (IDMC) met to monitor safety ofthe Tapinarof cream.

An interim analysis was carried out (database lock: 6 Jul. 2016) toidentify the appropriate drug concentration and topical applicationfrequency of Tapinarof for use in Phase III clinical studies. Theinterim analysis had originally been planned to be conducted when 100subjects had completed 8 weeks of treatment. However, due to GCPnoncompliance being discovered at 1 site (see Section 5.2.1), the numberof subjects required for the interim analysis was increased to 130 inorder to have approximately 100 subjects in the modified ITT (mITT)interim Population.

Discussion of Study Design

The randomized, double-blind (Sponsor-unblind), vehicle-controlled studydesign was selected to minimize the potential for subjective biasrelated to possible identification of which subjects were receivingactive treatment and to minimize selection and allocation bias bybalancing potential prognostic factors. The study was conducted atmultiple study centers to enhance the possibility of inclusion of awider range of population groups and to subsequently increasegeneralizability of the results.

Clinical studies in skin conditions have historically shown a notablevehicle (as well as placebo) response rate, which could be attributableto the effects of skin moisturization or to the increased emphasis onproper skin care while participating in a clinical study. A vehiclecontrol group was included in this study to provide a control forcomparison and to ensure study assay sensitivity for characterization ofthe safety and efficacy profile of Tapinarof cream.

The predicted maximum systemic exposure to Tapinarof in this study wasexpected to be lower than the no observed adverse effects level (NOAEL)identified in nonclinical toxicology studies. Exposure predicted basedon in vitro flux data and topical minipig relative bioavailabilityshowed a lesser systemic exposure for 1% cream formulation F versusFormulations C or E. This provided a safety margin of 4- to 8-fold forpredicted area under the concentration-time curve (AUC)₍₀₋₂₄₎ and 4- to6-fold for predicted maximum observed concentration (Cmax) for 1% cream(formulation F) applied BID when compared with the NOAEL obtained fromthe rat subcutaneous 3 mg/kg/day, 13-week toxicology study (99 ng·h/mLfor AUC(0-24) and 31.6 ng/mL for Cmax).

The treatment duration was 12 weeks. Previous studies of Tapinarof cream(using formulation C) showed some efficacy within the first 14 days oftreatment and increasing efficacy over 12 weeks of treatment. The12-week treatment endpoint in this study was expected to be an adequateduration of treatment to measure response and is in line with theduration of treatment in other studies of topical treatments forpsoriasis.

Inclusion Criteria: A subject was eligible for inclusion in this studyonly if all of the following criteria applied: 1. Male or female aged 18years to 65 years, inclusive, at the time of informed consent; 2.Clinical diagnosis of chronic stable plaque psoriasis for ≥6 months; 3.Body surface area involvement ≥1% and ≥15%, excluding scalp, atScreening and Baseline; 4. A PGA of psoriasis score ≥2 at Baseline; 5.One target plaque located on the trunk or proximal parts of extremities(excluding knees, elbows, and intertriginous areas) that was at least 3cm×3 cm in size at Screening and Baseline with a severity representativeof the subject's overall disease; 6. A female subject was eligible toparticipate if she was not pregnant (as confirmed by a negative urinehuman chorionic gonadotrophin [hCG] test), not lactating, and when atleast one of the following conditions applied: a. Non-reproductivepotential defined as: Pre-menopausal females with 1 of the following:documented tubal ligation, documented hysteroscopic tubal occlusionprocedure with follow-up confirmation of bilateral tubal occlusion,hysterectomy, documented bilateral oophorectomy; postmenopausal wasdefined as 12 months of spontaneous amenorrhea (in questionable cases ablood sample with simultaneous follicle stimulating hormone [FSH] andestradiol levels consistent with menopause [refer to laboratoryreference ranges for confirmatory levels]). Females on hormonereplacement therapy (HRT) and whose menopausal status was in doubt wererequired to use 1 of the highly effective contraception methods if theywished to continue their HRT during the study. Otherwise, they had todiscontinue HRT to allow confirmation of postmenopausal status prior tostudy enrolment. b. Reproductive potential and agreed to follow 1 of theoptions listed in the Modified List of Highly Effective Methods forAvoiding Pregnancy in Females of Reproductive Potential (FRP) from 30days prior to the first dose of study medication and until (at least 5terminal half-lives OR until any continuing pharmacologic effect hadended, whichever was longer) after the last dose of study medication andcompletion of the follow-up visit. The investigator was responsible forensuring that subjects understood how to properly use these methods ofcontraception.

Exclusion Criteria: A subject was not eligible for inclusion in thisstudy if any of the following criteria applied: 1. Any sign of infectionof any of the psoriatic lesions; 2. A history or ongoing serious illnessor medical, physical, or psychiatric condition(s) that, in theinvestigator's opinion, could have interfered with the subject'scompletion of the study; 3. Known hypersensitivity to the studytreatment excipients (for a detailed description of the ingredients ofthe study treatment, refer to, or a history of drug or other allergythat, in the opinion of the investigator, contraindicated participation;4. Current or chronic history of liver disease, known hepatic or biliaryabnormalities (with the exception of Gilbert's syndrome or asymptomaticgallstones), presence of hepatitis B surface antigen (HBsAg), orpositive hepatitis C antibody test result within 3 months of Screening;5. Liver function tests: alanine aminotransferase (ALT) ≥2× upper limitof normal (ULN); alkaline phosphatase and bilirubin >1.5×ULN (isolatedbilirubin >1.5×ULN was acceptable if bilirubin was fractionated anddirect bilirubin <35%); 6. QT interval corrected for heart rate (QTc)≥450 msec or QTc ≥480 msec for subjects with bundle branch block. TheQTc is the QT interval corrected for heart rate, with machine overread.The QTc was to be based on a single ECG obtained over a brief recordingperiod. If QTc was outside of the threshold value, triplicate ECGs couldbe performed with the QTc values averaged (see Protocol Section 7.4.5for information on QTc correction formula.) 7. Ultraviolet (UV) lighttherapy or prolonged exposure to natural or artificial sources of UVradiation (e.g., sunlight or tanning booth) within 4 weeks prior to theBaseline visit and/or intention to have such exposure during the study,which was thought by the investigator to potentially impact thesubject's psoriasis. 8. Used any of the following treatments within theindicated washout period before the Baseline visit: a. 12 weeks or 5half-lives (whichever was longer)—biologic agents (e.g., 24 weeks foralefacept, 12 weeks for etanercept, 15 weeks for ustekinumab); b. 12weeks—oral retinoids (e.g., acitretin or isotretinoin); c. 8weeks—cyclosporin, interferon, methotrexate, other systemicimmunosuppressive or immunomodulating agents, or psoralen plusultraviolet A (UVA) light treatment; d. 4 weeks—systemic corticosteroidsor adrenocorticotropic hormone analogs; e. 2 weeks—immunizations; drugsknown to possibly worsen psoriasis, such as β blockers (e.g.,propranolol), lithium, iodides, angiotensin-converting enzymeinhibitors, and indomethacin, unless on a stable dose for >12 weeks; f.2 weeks—topical treatments: corticosteroids, immunomodulators, anthralin(dithranol), Vitamin D derivatives, retinoids, or coal tar (used on thebody); 9. Participated in a clinical study and received aninvestigational product within the following time period prior to theBaseline visit: 4 weeks, 5 half-lives, or twice the duration of thebiological effect of the investigational product (whichever was longer);10. History of alcohol or other substance abuse within the last 2 years;11. Participated in a previous study using Tapinarof (GSK2894512 orWBI-1001).

Investigational Product and Reference Therapy: The term ‘studytreatment’ is used throughout this document to describe the product(i.e., Tapinarof or vehicle) received by subject as per the protocoldesign, as shown in Table 6.

TABLE 6 Investigational Product and Reference Therapy DrugDose/Form/Route Frequency/Duration Tapinarof 1% (10 mg/g), cream,topically BID, 12 weeks Tapinarof 1% (10 mg/g), cream, topically QD, 12weeks Tapinarof 0.5% (5 mg/g), cream, topically BID, 12 weeks Tapinarof0.5% (5 mg/g), cream, topically QD, 12 weeks Vehicle 0%, cream,topically BID, 12 weeks Vehicle 0%, cream, topically QD, 12 weeks

The list of excipients include are propylene glycol, diethylene glycolmonoethyl ether, polysorbate 80, medium chain triglycerides, emulsifyingwax non-ionic, polyoxyl stearyl ether 2, polyoxyl stearyl ether 20,benzoic acid, butylated hydroxytoluene, purified water, sodium citrate,citric acid monohydrate, and edetate disodium.

Primary Endpoint

The primary endpoint was the proportion of subjects who had a PGA scoreof clear or almost clear (0 or 1) at Week 12 and a minimum 2-gradeimprovement in PGA score from Baseline to Week 12.

Physician Global Assessment: The PGA is a clinical tool for assessingthe current state/severity of a subject's psoriasis. It is a static5-point morphological assessment of overall disease severity, asdetermined by the investigator, using the clinical characteristics oferythema, plaque thickness, and scaling as guidelines. At each specifiedtime point, the PGA is made without reference to previous scores.Variations of the PGA are frequently used in clinical studies because itis a simple assessment that is more similar to the assessments actuallyused in clinical practice. Scoring system ranges from 0 (=Clear) to 4(=Severe).

Secondary Endpoints

The secondary endpoints were the following: 1) Proportion of subjectswith ≥75% improvement in PASI from Baseline to each study visit; 2)Proportion of subjects with a minimum 2-grade improvement in PGA scorefrom Baseline to each study visit; 3) Proportion of subjects with a PGAscore of 0 or 1 at each study visit; 4) Mean change in % BSA affectedfrom Baseline to each study visit; 5) Mean change in PASI score fromBaseline to each study visit; 6) PGA scores at each study visit; 7) Meanchange in PGA score from Baseline to each study visit; 8) Mean change inindividual target lesion grading scores (erythema, scaling, andinduration) from Baseline to each study visit; 9) Mean change initch/pruritus NRS from Baseline to each study visit; 10) Proportion ofsubjects who achieve a PGA score of 0 or 1 and a minimum 2-gradeimprovement from Baseline to each study visit.

Psoriasis Area and Severity Index: The PASI scoring system is awidely-used standard clinical tool for assessing the severity ofpsoriasis that takes into account the overall severity of erythema(redness), thickness (induration), and scale, as well as the extent ofBSA affected with psoriasis. The 3 clinical signs are each graded on a 5point scale (0 to 4) and the % BSA affected is scored on a 7-point scale(0 to 6) for each of the 4 specified body regions (head, upperextremities, trunk, and lower extremities). The individual scores aremultiplied by a weighted factor for each body region; the sum of thesescores gives the overall PASI score. Higher scores indicate more severedisease. PASI is a static assessment made without reference to previousscores.

Body Surface Area: The extent of BSA affected by psoriasis is a generalindicator of disease severity and was measured throughout the study. Theextent of BSA to which study treatment was applied was also recorded.For the purpose of approximate clinical estimation, the total palmarsurface of the palm plus 5 digits was assumed to be approximatelyequivalent to 1% BSA.

Target Lesion Grading: A single target lesion was selected at Baselineto assess efficacy in treating a discrete area rather than an overallaverage of all areas. For that lesion, the severity of erythema,scaling, and plaque thickness was assessed by the investigator on a5-point scale ranging from “0=none” to “4=severe”.

Itch/Pruritus Severity: Subject-reported itch severity was obtained fromthe itch NRS item from the PSD.

Investigator Impression of Change Item: This was a single item thatasked the investigator to rate the change from Baseline in the subject'soverall psoriasis symptoms. Response options ranged from “1=veryimproved” to “7=very worse”. Results will also be used as a clinicalanchor in analyses of the minimally important differences in itch anddaily symptom severity.

Other Efficacy Endpoints: Other efficacy endpoints were as follows:Relationship between cream concentration and/or % BSA treated andchanges in systemic exposure as data permit. Proportions of subjects whoachieved a PGA score of 0 or 1 and a minimum 2 grade improvement fromBaseline at Week 12 and maintained the improvement at 2 and 4 weekspost-treatment. Proportions of subjects who achieved improvement withrespect to individual secondary efficacy endpoints at Week 12 andmaintained the improvement at 2 and 4 weeks post-treatment, asappropriate. Endpoints related to systemic exposure: Relationshipbetween systemic exposure and changes in efficacy (e.g., PGA score)and/or safety endpoints, as appropriate.

Pharmacokinetics: Sparse PK sampling throughout the duration of thestudy was intended to be used to develop a population PK model and toestimate population PK parameters (i.e., apparent clearance [CL/F],apparent volume of distribution [V/F]) of systemic exposure, accordingto the Time and Events Table. Plasma analysis was performed under themanagement of Bioanalysis, Immunogenicity & Biomarkers, IVIVT, PTS, GSK.

Health Outcomes

In order to evaluate symptoms and symptom impact, subjects completed thePSD daily as well as an overall severity of psoriasis symptoms item andglobal impression of change items (assessing change in severity ofpsoriasis symptoms and itch/pruritus). Each investigator also completeda global impression of change item (assessing change in severity ofpsoriasis symptoms) for each subject.

Psoriasis Symptom Diary (PSD): The PSD was developed to assess dailyself-reports of psoriasis symptoms and the functional impact related tothe underlying pathophysiology of the disease. Each item was rated usingan 11-point NRS. Questions asked about how severe and how bothersomevarious signs and symptoms were to the subject. The recall period wasthe last 24 hours. In addition to the 16 questions included in thealready established version of the PSD, 6 questions were added to assessthe severity and bother of skin flaking, dryness, and bleeding and weresimilar in wording to the items in the established version of the PSD.

Subject Impression of Severity and Change Items: At Baseline, subjectswere asked to rate the overall severity of their psoriasis symptoms on ascale ranging from “1=mild” to “4=very severe.” The global impression ofchange items asked subjects to rate their change from Baseline to Week12 in overall severity of psoriasis symptoms and in overall severity ofitch. Response options ranged from “1=very improved” to “7=very worse.”

Primary Efficacy Endpoint

The primary efficacy analyses were planned to be conducted on the mITTand PP Population, but since more than 95% of the PP Population was inthe mITT Population, no analyses were conducted on PP Population.

The study day relative to Day 1 was used as a covariate in the model.

The primary analysis was a repeated measures factorial logisticregression for the primary endpoint (proportion of subjects who had aPGA score of 0 or 1 at Week 12 and a minimum 2-grade improvement in PGAscore from Baseline to Week 12) with covariates for dose (0% forvehicle, 0.5% and 1%), frequency of administration (QD or BID), andstudy day as well as a dose by frequency interaction term. The responseat each visit was modeled as repeated measures via inclusion of a randomsubject effect. Estimated population mean dose/frequency-response curvesalong with their corresponding 95% confidence bands were provided forall dose levels and frequencies by time points of interest. Estimatedmean difference in response rate with 95% confidence interval betweenGSK2894512 and vehicle cream for BID and QD were provided by time pointsof interest.

Supportive statistical analyses of the primary endpoint based onJapanese subjects in the mITT Population was conducted for 2 frequencies(QD or BID) separately using simple logistic regression model withcovariate for dose (0% for vehicle, 0.5% and 1%). The same analysis wasdone for the overall mITT Population to compare the results of JapanesePopulation and Overall Population.

Summary statistics of the number of subjects providing data at therelevant time point, frequency counts and percentages, and 95% exactconfidence interval were provided for the PGA response rate for eachtreatment group at each study visit. Mean and 95% confidence intervalwere provided for the difference of (each BID dose −vehicle BID) and thedifference of (each QD dose−vehicle QD) in PGA response rate at eachvisit.

Secondary Efficacy Endpoints

The secondary efficacy analyses were based on the mITT Population,unless otherwise specified. The proportion of subjects who achieved aPGA score of 0 or 1 and a minimum 2-grade improvement from Baseline toeach study visit, the proportion of subjects with ≥75% improvement inPASI from Baseline to each study visit and the proportion of subjectswith ≥50% improvement in PASI from Baseline to each study visit wereanalyzed based on the mITT Population.

For continuous endpoints, a repeated measures Emax model with Integratedtwo-component prediction (ITP) time component was fitted to the data.All dichotomous secondary endpoints were modeled in the same logisticregression model described in the primary statistical analysis. Forcontinuous data, summary statistics of the mean, SD, median, minimum,maximum and number of observations were provided for each treatmentgroup at each study visit. For data of proportions, summary statisticsof the number of subjects providing data at the relevant time point,frequency counts and percentages, and 95% exact confidence interval wereprovided for each treatment group at each study visit. Mean and 95%confidence intervals were provided for the difference of (each BIDdose−vehicle BID) and the difference of (each QD dose−vehicle QD) in theproportion at each visit.

Demographics and Baseline Characteristics

Overall, mean demographic and Baseline characteristics were comparableacross treatment groups. Most subjects (80%) had a Baseline PGA categoryof “moderate” and a Baseline mean PASI score of 8.81 (standard deviation[SD] 4.472). Most Japanese subjects (75%) also had a Baseline PGAcategory of “moderate” and had a higher Baseline mean PASI score (12.44[SD 6.469]) than the Overall Population.

The vehicle QD group included a slightly smaller number of women thanthe rest of the groups (“gender” is not known to affect psoriasis).

The total number of subjects that completed the itch/pruritus NRS itemat Baseline was slightly smaller than the number of subjects for whichthere were other Baseline data available (190 vs 196, respectively).

Baseline PASI scores were higher in the 1% BID group in the Overall andJapanese Populations.

Baseline duration of psoriasis in the Japanese Population was slightlyshorter in the 1% (QD and BID) groups than the rest of the groups.

A total of 227 subjects (of the 290 subjects originally screened) wererandomized into the study at 17 sites in the United States, 12 sites inCanada, and 11 sites in Japan (intent-to-treat [ITT] analysispopulation). Of those randomized, 175 subjects (77%) completed the studyincluding the Week 16 follow-up visit. Overall, mean demographic andbaseline characteristics were comparable across treatment groups (Table7). Most subjects (80%) had a baseline PGA category of 3 (moderate) anda baseline mean Psoriasis Area and Severity Index (PASI) score of 8.8(SD 4.5). Primary endpoint: PGA response rates (defined as PGA score 0or 1 and ≥2-grade improvement) at Week 12 were higher in the tapinarofcream groups than the vehicle groups (65% [1% BID]; 56% [1% QD]; 46%[0.5% BID]; 36% [0.5% QD]; 11% [vehicle BID], and 5% [vehicle QD]) andwere maintained for 4 weeks after the end of study treatment.

TABLE 7 Baseline subject demographics and characteristics Tapinarof 1%Tapinarof 0.5% Vehicle BID QD BID QD BID QD (n = 38) (n = 38) (n = 38)(n = 38) (n = 37) (n = 38) Mean age, 45.9 (11.9) 48.5 (10.6) 49.6 (10.9)48.7 (9.7)  46.7 (12.6) 46.4 (10.2) years (SD) Male sex, 26 (68) 26 (68)24 (63) 25 (66) 23 (62) 29 (76) n (%) Mean 85.6 (22.5) 86.7 (22.6) 88.6(27.4) 89.3 (23.1) 87.8 (28.3) 91.6 (21.6) weight, kg (SD) PGA 2.9 (0.4)2.7 (0.5) 3.0 (0.5) 2.9 (0.4) 3.0 (0.3) 2.8 (0.4) score, mean (SD) PASI10.6 (5.0)  8.5 (3.6) 8.2 (4.5) 7.9 (4.8) 9.0 (4.3) 8.7 (4.4) score,mean (SD) BSA 8.2 (4.5) 6.5 (3.3) 7.2 (4.5) 6.1 (4.3) 6.6 (3.6) 7.0(4.6) affected, % (SD) Pruritus 5.6 (2.6) 4.4 (2.9) 6.2 (2.2) 4.5 (2.6)5.5 (2.8) 4.9 (2.4) score, mean (SD)* *Mean scores based on a scale of 0‘absent’ to 10 ‘worst imaginable’. Demographics provided for the safetyanalysis population (n = 227) and characteristics provided for the mITTanalysis population (n = 196). The mITT analysis population includedsubjects in the ITT population minus the subjects from one site due toconcerns regarding data accuracy. BID, twice daily; BSA, body surfacearea; ITT, intent-to-treat; mITT, modified intent-to-treat; PASI,Psoriasis Area and Severity Index; PGA, Physician Global Assessment; QD,once daily; SD, standard deviation.

Efficacy Results

Efficacy results are reported using the mITT Population. No analysisbased on the PP Population was conducted since more than 95%(188/196=96%) of the PP Population was in the mITT Population. Unlessmentioned otherwise, results reported in this section are those of theOverall Population and refer to observed cases (OC) imputation method.

Interim Analysis: A “go” decision was reached based on a clinicallymeaningful efficacy profile and a well-tolerated safety profile (theanalysis included 100 subjects): Response rates of 42%, 32%, 36%, 46% atWeek 8 for the primary endpoint with GSK2894512 cream concentrations 100BID, 1% QD, 0.5% BID, 0.5% QD, respectively, and 0% for vehicle BID andvehicle QD. Efficacy responses were better at each study visit in the 1%concentration based on PASI. Mild to moderate application site reactions(folliculitis and contact dermatitis) as the main AEs.

Physician Global Assessment (PGA): The primary objective of this studywas to estimate the relationship between Tapinarof cream concentrations(0.5% and 1%) and application frequency (QD or BID) with efficacyresponse based upon clinical evaluation in subjects with plaquepsoriasis. The primary endpoint was the proportion of subjects who had aPGA score of clear or almost clear (0 or 1) at Week 12 and a minimum2-grade improvement in PGA score from Baseline to Week 12.

The planned repeated measures factorial logistic regression model withITP did not fit the data well. Therefore, summary statistics of thenumber of subjects providing data at the relevant time point, frequencycounts and percentages, and 95% exact confidence interval were providedfor the PGA response rate for each treatment group at each study visit.Mean and 95% confidence interval were provided for the difference of(each BID dose−vehicle BID) and the difference of (each QD dose−vehicleQD) in PGA response rate at each visit.

The primary endpoint analysis showed a higher proportion of subjects inthe active treatment groups than in the vehicle groups at Week 12. The1% concentration treatment groups showed a higher rate of response thanthe 0.5% concentration groups. PGA response rates (treatment successdefined by PGA score 0 or 1 and a minimum 2-grade improvement) at Week12 were statistically significantly higher (at 0.05 significance level)in the tapinarof groups than the vehicle groups (65% [1% BID]; 56% [1%QD]; 46% [0.5% BID]; 36% [0.5% QD]; 11% [vehicle BID], and 5% [vehicleQD] (FIG. 6 ). Differences between active and vehicle were (95% CI):54.7% (25.9%, 76.6%) [1% BID-vehicle BID], 51.0% (22.2%, 73.2%) [1%QD-vehicle QD], 35.6% (6.3%, 60.5%) [0.5% BID-vehicle BID], 30.7% (1.6%,55.9%) [0.5% QD-vehicle QD]). PGA treatment success was statisticallysignificantly greater (at 0.05 significance level) in the tapinaroftreatment groups than in the vehicle groups at Week 12 and wasmaintained for 4 weeks after the end of study treatment—Week 16 exceptfor the 0.5% BID group (58% [1% BID]; 54% [1% QD]; 35% [0.5% BID]; 36%[0.5% QD]; 5% [vehicle BID], and 0 [vehicle QD] (FIG. 6 ).

PGA secondary endpoint analyses revealed: An increasing proportion ofsubjects who had a minimum 2-grade improvement in PGA score fromBaseline to each study visit in the active treatment groups comparedwith the vehicle groups. The 1% concentration treatment groups showed ahigher rate of responders than the 0.5% concentration groups at Week 12.

An increased proportion of subjects who had a PGA score of 0 or 1 and aminimum 2-grade improvement in PGA scores from Baseline to Week 12 andmaintained the improvement at 2 and 4 weeks post-treatment in the activetreatment groups compared with the vehicle groups. The 10% concentrationtreatment groups showed a higher rate of responders than the 0.5%concentration groups. Specifically, 67% (10 of 15) of subjects in the 1%BID group and 86% of subjects (12 of 14) in the 1% QD group maintainedresponse from Week 12 to Week 16. This secondary endpoint resultindicates a durability of the effect of Tapinarof cream after the12-week treatment period, and a sustained PGA treatment response.

An increasing proportion of subjects who had a PGA score of 0 or 1 ateach study visit in the active treatment groups compared with thevehicle groups. The 1% concentration treatment groups showed a higherrate of responders than the 0.5% concentration groups at Week 12.

Decreasing PGA scores at each study visit in the active treatment groupscompared with the vehicle groups.

Increasing mean change reductions in PGA scores from Baseline to eachstudy visit in the active treatment groups compared with the vehiclegroups.

Psoriasis Area and Severity Index (PASI): The main secondary objectiveof this study was to estimate the efficacy of GSK2894512 cream. The mainsecondary endpoint was the proportion of subjects with ≥75% improvementin PASI (PASI75) from Baseline to each study visit.

The planned repeated measures factorial logistic regression model withITP did not fit the data well. Therefore summary statistics of thenumber of subjects providing data at the relevant time point, frequencycounts and percentages, and 95% exact confidence interval were providedfor the PASI75 response rate for each treatment group at each studyvisit.

Mean and 95% confidence interval were provided for the difference of(each BID dose−vehicle BID) and the difference of (each QD dose−vehicleQD) in PASI75 response rate at each visit.

The main secondary endpoint analysis showed a higher proportion ofsubjects in the active treatment groups than in the vehicle groups. The1% concentration treatment groups showed a higher rate of respondersthan the 0.5% concentration groups, using the OC and LOCF imputationmethods.

PASI secondary endpoint analyses revealed: A higher increasing meanpercent change reduction in PASI scores from Baseline to each studyvisit in the active treatment groups than in the vehicle groups. The 1%concentration treatment groups showed a higher mean percentage changereduction than the 0.5% concentration groups at all visits.

The mean percent change reductions in PASI scores from Baselinecontinued to improve over time. The effects of Tapinarof cream on thisparameter after QD and BID applications were similar.

An increased proportion of subjects with ≥75% improvement in PASI fromBaseline to Week 12 was observed and this improvement was maintained at2 and 4 weeks post-treatment in the active treatment groups comparedwith the vehicle groups. The 1% concentration treatment groups showed amore sustained improvement than the 0.5% concentration groups.Specifically, 80% (12 of 15) of subjects in the 1% BID group and 93% ofsubjects (12 of 14) in the 1% QD group maintained response from Week 12to Week 16. This secondary endpoint result indicates a durability of theeffect of Tapinarof cream after the 12-week treatment period, and asustained PASI treatment response.

Psoriasis Area and Severity Index (PASI) Ad hoc Analysis

Analyses of PASI endpoints PASI90, PASI=0, PASI≤1, PASI≤3 revealed: Ahigher proportion of subjects reached each endpoint in the activetreatment groups than in the vehicle groups. The 1% concentrationtreatment groups showed a higher rate of responders than the 0.5%concentration groups, using OC data.

PASI90, PASI=0, PASI≤1, PASI≤3 continued to improve over time.

The effects of GSK2894512 cream on these endpoints (PASI90, PASI=0,PASI≤1 and PASI≤3) after QD and BID applications were similar.

Body Surface Area (BSA): A secondary objective was to assess the meanchange in percent of total BSA affected from Baseline to each studyvisit.

An increase in the mean change reduction in percent of total BSAaffected from Baseline to each study visit was higher in the activetreatment groups than in the vehicle groups.

The increase in the mean change reduction in percent of total BSAaffected from Baseline continued to improve over time. The effects ofGSK2894512 cream on the mean change reduction in percent of total BSAaffected from Baseline to each study visit after QD and BID applicationswere similar.

Target Lesion Grading: A secondary objective of the study was to assessthe mean change in total target lesion grading scores (erythema, scalingand induration/plaque thickness) from Baseline to each study visit.

An increase in the mean change reduction in total target lesion gradingscores from Baseline to each study visit was higher from Week 2 in theactive treatment groups than in the vehicle groups. Table 8 provides asummary of psoriasis target lesion grading scale.

TABLE 8 Summary of Psoriasis Target Lesion Grading Scale Percent changefrom Baseline Tapinarof Tapinarof Tapinarof Tapinarof 1% 1% 0.5% 0.5%Vehicle Vehicle cream cream cream cream cream cream twice once twiceonce twice once Visit Category daily daily daily daily daily daily Week1 Erythema Mean −12.50 −17.14 −9.95 −14.25 −6.55  −3.13 Scaling Mean−25.00 −24.29 −12.37 −20.97 −17.26  −9.38 Plaque Mean −18.75 −13.10−14.52 −10.22 −14.29  −5.21 thickness Week 2 Erythema Mean −25.52 −35.68−23.61 −28.13 −7.25  −4.94 Scaling Mean −32.55 −32.81 −35.00 −34.38−33.33  −8.95 Plaque Mean −33.33 −30.47 −33.89 −26.04 −21.01  −8.33thickness Week 4 Erythema Mean −44.94 −51.88 −45.54 −35.48 −19.05 −11.22Scaling Mean −55.65 −53.49 −50.89 −51.34 −36.51 −13.46 Plaque Mean−48.51 −47.04 −44.64 −42.47 −33.33 −14.42 thickness Week 8 Erythema Mean−62.50 −65.06 −62.33 −50.81 −28.70 −15.28 Scaling Mean −70.51 −71.79−60.00 −68.01 −44.44 −16.20 Plaque Mean −62.82 −60.90 −62.67 −60.75−35.19 −18.06 thickness Week Erythema Mean −77.65 −81.88 −76.52 −65.06−18.42 −22.81 12 Scaling Mean −78.79 −83.33 −78.03 −72.76 −34.21 −25.88Plaque Mean −81.82 −70.29 −71.59 −67.31 −35.96 −25.88 thickness Follow-Erythema Mean −65.42 −70.65 −68.25 −63.77 −19.79 −31.86 up/ Week ScalingMean −67.50 −67.39 −68.65 −67.75 −21.88 −23.04 14 Plaque Mean −67.50−70.29 −67.86 −67.39 −30.21 −27.94 thickness Follow- Erythema Mean−78.33 −74.24 −59.47 −73.96 −20.37 −15.74 up/ Scaling Mean −77.50 −71.59−57.95 −69.79 −21.30 −12.96 Week Plaque Mean −76.67 −65.91 −54.92 −71.53−24.07 −17.59 16 thickness Erythema Mean −46.67 −47.62 −25.00  8.33−18.33  −1.85 Early Scaling Mean −52.50 −57.14 −41.67 −16.67 −16.67 −3.70 WD Plaque Mean −46.67 −60.71 −33.33  0.00 −20.00  20.37 thickness

Itch/Pruritus Severity: A secondary objective of the study was to assessthe mean change in weekly itch/pruritus NRS item from Baseline to eachstudy visit.

There was no clear difference in the mean change reduction initch/pruritus from Baseline to each study visit between the activetreatment groups compared to the vehicle groups. The same pattern wasobserved for subjects with a Baseline NRS score ≥4. Additionally, noclear difference was observed in the proportion of subjects with aBaseline NRS score ≥who achieved a minimum 4-point improvement initch/pruritus NRS from Baseline to each study visit between the activetreatment groups and the vehicle groups. A BID application appeared tobe more beneficial when compared to vehicle. Overall, most patients hada decrease (minimum 4-point improvement) in itch/pruritus symptoms overthe study period.

Severity of Psoriasis Symptoms: One of the secondary endpoints assessedduring the study was the change over time in weekly psoriasis symptomsas recorded daily in the PSD. The PSD includes 16 items from the alreadyestablished version of the PSD as well as 6 newly developed items.

Overall, mean change reduction in the weekly average scores from the PSDwas generally higher in the active treatment groups than in the vehiclegroups. Of interest, PSD questions #2, #11, #12, #13, #14, #17, #18, #19and #20 revealed a high mean severity score (5.0 or above) at Baseline;by Week 12, scores from these items had reduced (improved) more in theactive treatment groups compared with the vehicle groups.

Investigator Impressions: As part of the efficacy assessment,investigators' impressions of change in psoriasis symptom severity fromBaseline to Week 12 were reported. Responses were rated by investigatorsas “very improved” or “moderately improved” in >80% of subjects in the1% concentration groups and 76% to 85% in the 0.5% concentration groups.In the “very improved” category, a clear difference was observed betweenthe active treatment groups and the vehicle groups.

Subject Impressions: A secondary endpoint was to monitor subjectimpressions of change in psoriasis symptom severity from Baseline toWeek 12.

At baseline, 88% of subjects rated their psoriasis symptoms as moderateor severe across all treatment groups: 43-61% rated as moderate and28-44% rated as severe. At Week 12, most subjects in the tapinarof creamgroups (82-88% in the 1% groups and 77-80% in the 0.5% groups) rated theseverity of their overall psoriasis symptoms as ‘very improved’ or‘moderately improved’ compared with 35-48% in the vehicle groups (FIG. 7). The majority of subjects treated with tapinarof cream (70-76% in the1% groups and 73-77% in the 0.5% groups) rated the severity of theirpruritus symptoms as ‘very improved’ or ‘moderately improved’ comparedwith 35-47% in the vehicle groups at Week 12 (FIG. 8 ).

Between 43% and 61% of subjects rated their Baseline psoriasis symptomsas moderate. At Week 12, most subjects in the Tapinarof groups (>80% inthe 1% concentration groups and between 77-80% in the 0.5% concentrationgroups) rated the severity of their overall psoriasis symptoms as “veryimproved” or “moderately improved.” Similarly, most subjects in theTapinarof groups (70-77% in the 1% and 0.5% concentration groups) ratedthe severity of their itch symptoms as “very improved” or “moderatelyimproved.”

Sub-group Efficacy Analysis: Japanese Population: Out of the 227subjects randomized in this study, 36 subjects were Japanese.

Primary and main secondary endpoint analyses for the Japanese sub-groupwere consistent with the Overall Population.

Global Assessment (PGA): The primary efficacy endpoint, the proportionof subjects who had a PGA score of 0 or 1 and a minimum 2-gradeimprovement in PGA score from Baseline to Week 12 was higher in theactive treatment groups than in the vehicle groups. The 1% concentrationtreatment groups showed a higher proportion of responders than the 0.5%concentration groups, using the OC and the LOCF imputation methods. Noresponders were observed in the vehicle groups.

Psoriasis Area and Severity Index (PASI): The main secondary efficacyendpoint, the proportion of subjects with ≥75% improvement in PASI fromBaseline to each study visit was higher in the active treatment groupsthan in the vehicle groups (apart from Week 4, when the vehicle BIDgroup exceeded both GSK2894512 0.5% groups). The 1% concentrationtreatment groups showed a higher percentage of subjects with ≥75%improvement than the 0.5% concentration groups, in the OC and LOCFimputation methods.

Similarly, the increasing mean percent change reduction in PASI scoresfrom Baseline to each study visit was higher in the active treatmentgroups than in the vehicle groups. The 1% concentration treatment groupsshowed a higher mean percentage change reduction than the 0.5%concentration groups with the OC and LOCF imputation methods.

Pharmacokinetics: One of the secondary objectives of this study was tocharacterize the population PK of GSK2894512 cream after topicalapplication. Bioanalysis of the plasma samples from 225 subjects wasperformed. All PK samples were analyzed; however, all results were ‘notreportable (NR)’ due to the ISR failing to meet the acceptance criteria.

The bioanalytical method used to support the study was a fully validatedLiquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method inaccordance with FDA/EU/MHLW guidelines [US Department of Health andHuman Services, Food and Drug Administration Draft Guidance forIndustry: Bioanalytical Method Validation, 2013] [European MedicinesAgency Guideline on Bioanalytical Method Validation, 2011] [JapaneseMinistry of Health Guideline on Bioanalytical Method Validation inPharmaceutical Development, 2013].

One hundred and fifty samples (17% of total number of samples) werere-analyzed for ISR evaluation. It was observed that 55% of the ISRrepeat results and original results were within 20% of the mean of the 2values; this was not within the acceptance criteria (more than 66% ofnumber of samples should be within 20%). The ISR investigation providedno assignable cause to explain the high variability on re-analyzingstudy samples. Further investigation of ISR failure could not beperformed due to the sample depletion.

Plasma concentrations were measured for 860 samples from patientsreceiving an active dose of Tapinarof; 649 samples were below the LowerLimit of Quantitation (LLQ), 54 samples were not measurable and 157samples were quantified. Based on the available data, the plasmaconcentrations samples fell mainly within the region of the assay LLQ.Generally, there was an aspect of the bioanalytical methodology that ledto variability (e.g., extraction) in the region near the LLQ. In fact,the acceptance criteria for accuracy and precision at LLQ were 20% widerthan at higher concentrations (15%) according to MHLW guideline.Therefore, lower exposures in psoriasis may likely have contributed tothe ISR variability. Additionally, these lower levels of systemicexposures were not unexpected as a low total BSA was treated in thestudy (6.32%).

As a result of the NR data, one of the secondary objectives of thestudy, the exploration of the relationship between topical application(as cream concentration and % BSA treated), efficacy and/or safety, andsystemic exposure of Tapinarof, was not met.

An increased understanding of PK for both indications will come from theplanned maximum use pharmacokinetics (MUPK) studies, which will use anew bioanalytical method with a lower LLQ.

Safety Results

Safety results are reported using the Safety Population. Unlessmentioned otherwise, results reported in this section are those of theOverall Population.

Adverse Events: Treatment-emergent adverse events (TEAEs) were reportedin 104 subjects (46%) (the Safety Population comprised 227 subjects).The frequency of TEAEs was higher in the active treatment groups than inthe vehicle groups (85/152 subjects [56%] vs 19/75 subjects [25%]).

TEAEs were considered treatment-related in 36/227 subjects (16%); mostof these subjects were in the active treatment groups compared with thevehicle treatment groups (34/152 [22%] vs 2/75 [3%]) (approximately 33%females and 67% males). Sixteen of 227 subjects (7%) permanentlydiscontinued treatment due to TEAEs (15/152 [10%] in the activetreatment groups vs 1/75 [1%] in the vehicle treatment groups). Sevensubjects (3%) experienced serious TEAEs (all were reported from theactive treatment groups). Treatment-emergent adverse events (TEAEs) werereported in 46% of patients (68% [1% BID]; 53% [1% QD]; 58% [0.5% BID];45% [0.5% QD]; 24% [vehicle BID], and 26% [vehicle QD]) with most TEAEsreported as mild to moderate intensity. The most commonly (≥5%) reportedTEAEs (regardless of relationship to study treatment) were folliculitis(20/227, 9% [19/152, 13% tapinarof groups and 1/75, 1% vehicle groups])and contact dermatitis (12/227, 5%; all in the tapinarof groups [12/152,8%]). Folliculitis was also the most frequent (≥5%) treatment-related260 TEAE (16/227, 7% overall; 15/152 [10%] tapinarof groups vs 1/75 [1%]vehicle groups). Other treatment related TEAEs were: contact dermatitis(3%) (all tapinarof groups) and application site dermatitis, applicationsite irritation, allergic dermatitis, monocyte count decreased andheadache (1% each) (all tapinarof groups except for one case of monocytecount decreased, occurring in a vehicle patient). TEAEs led to permanentdiscontinuation of study treatment in 16/227 (7%) patients (15/152 [10%]tapinarof groups vs 1/75 [1%] vehicle groups). Contact dermatitis wasthe most common reason for study treatment permanent discontinuation,occurring in 6/227 (3%) of patients (all in tapinarof groups), patchtesting was not performed to evaluate if these were cases of allergic orirritant contact dermatitis. Two patients treated with 1% tapinarof(1-QD group, 1-BID group) permanently discontinued treatment due to‘application site dermatitis’. Tolerability improved from Week 1 to Week12 in both concentration groups (0.5% and 1%) and with both frequenciesof application (QD or BID). The 1% QD treatment may have a slightlybetter tolerability profile than the 1% BID treatment, based on a lowerfrequency of TEAEs. Eight SAEs (alcoholic pancreatitis, dehydration,malignant melanoma [not at application site], hemolytic uremic syndrome,coronary artery disease, enlarged uvula, acute cardiac failure andatrial fibrillation) were reported in 7 patients (3%), all in tapinarofgroups, none were treatment-related judged by the investigators. Allpatients, except the patient with malignant melanoma, had a pre-existingillness related to the event. In addition, there were noclinically-significant differences in mean changes in vital signs, ECGparameters, and laboratory evaluations between study groups during thestudy.

Most TEAEs were reported as mild (41/152 [27%] in the active treatmentgroups vs 13/75 [17%] in the vehicle treatment groups) or moderate(33/152 [22%] in the active treatment groups vs 4/75 [5%] in the vehicletreatment groups). Thirteen subjects (6%) experienced severe TEAEs(11/152 [7%] in the active treatment groups vs 2/75 [3%] in the vehicletreatment groups). None of the serious TEAEs were treatment-related.

The most frequently reported TEAE was folliculitis, which occurred in 20subjects (9%) (19/152 [13%] in the active treatment groups vs 1/75 [1%]in the vehicle treatment groups). Other TEAEs included contactdermatitis, reported in 12 subjects (5%); (all reported in the activetreatment groups), nasopharyngitis, reported in 9 subjects (4%) (7/152[5%] in the active treatment groups vs 2/75 [3%] in the vehicletreatment groups), headache in 8 subjects (4%) (6/152, [4%] in theactive treatment groups vs 2/75 [3%] in the vehicle treatment groups)and vomiting, reported in 4 subjects (2%) (3/152 [2%] in the activetreatment groups vs 1/75 [1%] in the vehicle treatment groups).

The following TEAEs were each reported in 3 subjects (1%) each: atrialfibrillation (1 subject in the 1% QD group, 1 in the 0.5% BID and 1 inthe vehicle group; none had any relevant medical history), hypertension(1 subject in the 1% QD group, 1 in the 1% BID and 1 in the 0.5% BIDgroup; none had any prior medical history), acne, application sitedermatitis, application site irritation, arthralgia, laceration,miliaria, back pain, allergic dermatitis, gastritis, ligament sprain,monocyte count decreased, pruritus, upper respiratory tract infectionand urticaria.

TEAEs considered treatment-related by the investigators consisted mainlyof folliculitis, which occurred in 16 subjects (7%) (15/152 [10%] fromthe active treatment groups vs 1/75 [1%] from the vehicle treatmentgroups (approximately 7% females and 7% males had this TEAE). Othertreatment-related TEAEs were: contact dermatitis in 7 subjects (3%) (allin the active treatment groups), application site dermatitis andapplication site irritation, in 3 subjects each (1% each)(all in theactive treatment groups), allergic dermatitis in 2 subjects (1%) (bothin the active treatment groups), monocyte count decreased in 2 subjects(1%) (1/152 [1%] in the active treatment groups vs 1/75 [1%] in thevehicle treatment groups) and headache in 2 subjects (1%)(both in theactive treatment groups).

Treatment-emergent AEs led to permanent discontinuation of studytreatment in 16 subjects (7%). The frequency was higher in the activetreatment groups than in the vehicle groups (15/152 [10%] in the activetreatment groups vs 1/75 [1%] in the vehicle treatment groups). Contactdermatitis was the most frequent TEAE that led to study treatmentdiscontinuation; it was reported in 6 subjects (3%), all in the activetreatment groups, 5 of whom were treated with the higher GSK2894512cream concentration (1% QD and BID), and 1 was treated with GSK2894512cream 0.5% QD. Application site dermatitis was the next most frequentTEAE leading to study treatment discontinuation; it was reported in 2subjects, both of them treated at the higher GSK2894512 creamconcentration (1% QD and BID).

Serious and Other Significant Adverse Events

Deaths: No deaths were reported during the study.

Other Serious Adverse Events: Serious TEAEs were reported in 7 subjects(3%), all of whom were in the Tapinarof treatment groups Brief summariesof these serious TEAEs are provided below.

Acute cardiac failure and atrial fibrillation: A 55-year-old male with aprevious history of diabetes mellitus, hyperlipidemia, and atrialfibrillation was randomized to receive Tapinarof 0.5% BID. The subjectwas hospitalized due to acute cardiac failure and atrial fibrillation 53days after the first application. Study treatment was interrupted for 4days. The subject was treated and events were resolved 40 days later.The investigator considered the events were unrelated to studytreatment.

Alcoholic pancreatitis: A 42-year-old male was randomized to receiveTapinarof cream 1% BID. The subject experienced abdominal pain, nauseaand vomiting and was hospitalized due to acute pancreatitis 5 days afterthe first application of study treatment. He reported several recentcelebrations and had increased his alcohol intake during that time. Hewas treated with ondansetron, pantoprazole, intravenous fluids andmorphine. Study treatment was continued. The event resolved after 2days. The investigator considered that the event was not related tostudy medication.

Dehydration: A 37-year-old male was hospitalized due to dehydration(grade 3) 49 days after the first application of Tapinarof cream 0.5%BID. The subject ingested large quantities of beer 24 hours before theevent; he was outdoors on a hot day and did not stay hydrated. Thesubject received intravenous fluids and dehydration resolved on the sameday. The investigator considered that the event was unrelated to thestudy treatment.

Malignant melanoma: A 58-year-old male with a history of sun exposureand a sister with a history of malignant melanoma received Tapinarofcream 0.5% BID. The subject developed grade 3 malignant melanoma in ananatomically distinct area separate from the site of study treatmentapplication, 16 days after the first application of study treatment.Study treatment was continued. Surgery was performed and the eventresolved after 28 days. The investigator considered that the event wasunrelated to study treatment.

Hemolytic uremic syndrome: A 43-year-old male with a personal and familyhistory of hemolytic uremic syndrome due to an inherited enzymedeficiency received Tapinarof cream 1% QD. The subject was hospitalizeddue to grade 3 renal failure 59 days after the first application ofstudy treatment. The event resolved and the subject was discharged after2 days. No abnormalities were observed at any of the subject's scheduledlaboratory investigations. The investigator considered that the eventwas not related to study treatment.

Coronary artery disease: A 61-year-old male experienced grade 3 coronaryartery disease 80 days after the first application of Tapinarof cream 1%QD. The subject was hospitalized. He had a history of coronary arterybypass surgery, diabetes mellitus, hypercholesterolemia, andhypertension. Study treatment was discontinued and the subject wastreated with furosemide, clopidogrel, perindopril, and metoprolol. Theevent resolved 10 days later. The investigator considered that the eventwas unrelated to study treatment.

Enlarged uvula: A 52-year-old male was hospitalized due to uvulaswelling (grade 3) 9 days after the first application of Tapinarof cream1% QD. The subject had a history of unreported intermittent uvulaswelling since beginning lisinopril treatment, and was taking lisinoprilduring the study. The subject was treated with methylprednisolone sodiumsuccinate, diphenhydramine, famotidine, sodium chloride, paracetamol,dexamethasone, and zolpidem tartrate. Tapinarof cream was continued. Theevent resolved 2 days later. The investigator considered that the eventwas not related to the study treatment.

Other Significant Adverse Events: No other significant AEs were reportedduring the study. However, a summary of the details of the 4 mostfrequently reported AEs is provided below.

Folliculitis: A total of 20 out of 227 (9%) subjects (15 male, 5 female;aged between 21 to 63 years), experienced folliculitis, 19 from theactive treatment and 1 from the vehicle groups. Most of these eventswere reported from GSK2894512 1% BID group (8/20, 40%). A majority ofthe events were mild (15/20, 75%) and the rest were considered moderate(5/20, 25%). No severe events were reported. Treatment was withdrawn inone subject due to the event. Most (14/20, 70%) of the events occurredat the study drug application site. The median time to onset (sinceDay 1) was 24.5 days (26 days in the active treatment groups and 8 daysin the vehicle groups). Fifteen (75%) cases were considered eitherresolved or resolving at the time of the report. Where the eventresolved, the median duration of the event was 48.5 days (55 days in theactive treatment groups and 7 days in the vehicle groups). A majority(16/20, 80%) of these events were considered related to study treatmentby the investigators.

Contact dermatitis: A total of 12 out of 227 (5%) subjects (7 male, 5female; aged between 29 to 61 years) experienced contact dermatitis, allfrom the active treatment groups. Three of the 12 subjects experiencedirritant contact dermatitis. Most of these events were reported fromTapinarof 1% groups (8/12, 67%), 4/12 (33%) from the 1% BID group and4/12 (33%) from the 1% QD group. A majority of the events were ofmoderate intensity (7/12, 58%), 4/12 (33%) were considered mild and 2/12(17%) were considered severe. Six subjects (6/12, 50%), including 2subjects with irritant contact dermatitis, had treatment withdrawn dueto the event. At the time of the report, events were ongoing in 1subject, had an unknown outcome in 1 subject and were considered eitherrecovered or resolved in 10 (83%) subjects. Half (6/12, 50%) of theevents occurred at the study drug application site. The median time toonset (since Day 1) was 30 days. The median duration of the event was 32days. Over half (7/12, 58%) of these events were considered related tostudy treatment by the investigators.

Nasopharyngitis: A total of 9 out of 227 (4%) subjects (7 male, 2female; aged between 33 to 65 years) experienced nasopharyngitis, 7 ofwhom (7/9, 78%) were from the active treatment groups. Most of theseevents were reported from Tapinarof 0.5% BID group (4/9, 44%), 2 fromthe Tapinarof 0.5% QD group (2/9, 22%), 1 from the GSK2894512 1% BIDgroup (1/9, 11%), and 2 from the vehicle groups (2/9, 22%). A majorityof the events were of mild intensity (7/9, 78%) and 2 (2/9, 22%) wereconsidered moderate in intensity. No subjects had treatment withdrawndue to the event and no events were ongoing at the time of reporting(all cases were considered recovered or resolved at the time of thereport). The median time to onset (since Day 1) was 45 days (13 days inthe active treatment groups and 63.5 days in the vehicle groups). Themedian duration of the event was 7 days (12 days in the active treatmentgroups and 7 days in the vehicle groups). None of the events wereconsidered related to study treatment by the investigators.

Headache: A total of 8 out of 227 (4%) subjects (6 male, 2 female; agedbetween 29 to 60 years) experienced headache, 6/8 (75%) from the activetreatment groups and 2/8 (25%) from the vehicle groups. Half of theseevents were reported from Tapinarof 1% BID group (4/8 [50%]). Themajority of the events (6/8, 75%) were of a mild nature, 1 (1/8, 13%)was considered moderate and one (1/8, 13%) was considered severe. Nosubjects had treatment withdrawn due to the event and no events wereongoing (all cases were considered recovered or resolved) at the time ofreporting. The median time to onset (since Day 1) was 5 days (2.5 daysin the active treatment groups and 60 days in the vehicle groups). Themedian duration of the event was 1 day (3 days for the active treatmentgroups and 1 day for the vehicle groups). Two (2/8, 25%) of the eventswere considered related to study treatment by the investigators.

Clinical Laboratory Evaluations

No clinically-significant changes in laboratory evaluations werereported during the study.

Four subjects experienced ALT and/or AST elevation >2×ULN; two each inactive and vehicle treatment groups. Of these four patients, one (a51-year-old female) in the Tapinarof cream 1% BID group had ALT >3×ULNapproximately 1 month after the first exposure to study treatment (Week4). The elevation did not meet the liver stopping criteria and the studytreatment was continued. The event resolved after 20 days. Of theremaining three patients, one had AST >2×ULN and two had ALT >2×ULN.Except in one patient, the elevated AST or ALT values resolved within 2weeks despite study treatment continuation.

Two patients (a 19- and a 29-year-old, both with baseline bilirubinlevels above normal), had bilirubin elevations over 1.5×ULN. Both ofthem were treated in the vehicle groups. These abnormalities were notaccompanied by ALT/AST abnormalities. The event resolved after 2 weeksin one of the patients (the 29-year-old) and remained elevatedthroughout the study in the other patient (the 19-year-old).

Other Safety Evaluations: No clinically-significant ECGs were observedin this study. A summary of change from Baseline in ECG values over timedid not demonstrate any abnormalities.

Tolerability Evaluations: One of the secondary objectives of the studywas to describe the tolerability of Tapinarof cream by measuring local(application site) tolerability scores as a secondary endpoint.

No difference in tolerability scores was reported by subjects betweenthe 2 Tapinarof cream concentrations (0.5% and 1%) or between the 2frequencies of application (QD or BID) tested. Tolerability scoresimproved during the course of the study. The proportion of subjects withthe best tolerability score (score 0 or “none”) increased from Week 1 toWeek 12 across all study treatment groups. The number of subjects whopermanently discontinued the study treatment due to potentialtolerability issues was relatively small (approximately 8 subjects intotal), which does not affect the interpretation of the overalltolerability trend.

Investigators assessed most subjects (≥70%) as having the lowestirritation score (0 or “no irritation”) from Week 1 onwards.

Pregnancies: No pregnancies were reported during the study.

Immunoglobulins and Immunophenotyping: No clinically-significant changeswere observed in Immunoglobulins (IgA, IgG, and IgM) across alltreatment groups receiving either Tapinarof or vehicle and regardless ofdosing frequency.

No clinically-significant changes were observed in Immunophenotypingacross all treatment groups receiving either Tapinarof or vehicleregardless of dosing frequency.

Health Outcomes

One of the objectives of this study was to describe the effect ofTapinarof cream on subject-reported outcomes, for which subjectscompleted the PSD (including the NRS itch/pruritus item) as well as 2global impressions of change items

Discussion and Conclusions

Discussion

The objective of this randomized, double-blind, vehicle-controlled PhaseII study was to evaluate the efficacy and safety of 2 doses of Tapinarofcream (0.5% or 1%) applied either QD or BID in adult subjects withpsoriasis over 12 weeks. The characterization of population PK ofTapinarof cream after topical application was also an objective of thestudy; however, plasma concentrations were not reported mainly due tothe ISR failing to meet the acceptance criteria. Bioanalysis and datawere not reported.

Study Population: The population enrolled in this study was consistentwith a moderate to severe psoriasis patient population. Specifically,subjects had a mean PGA score of 2.9 and 3.0 in the overall and theJapanese populations, respectively. Demographic and Baselinecharacteristic were generally similar across treatment groups.

Efficacy Discussion

Treatment success defined by PGA 0 or 1 and a 2-Grade Improvement atWeek 12 were statistically significantly higher (at a 0.05 significancelevel) in the tapinarof groups than the vehicle groups: (65% [1% BID];56% [1% QD]; 46% [0.5% BID]; 36% [0.5% QD]; 11% [vehicle BID], and 5%[vehicle QD]) and was maintained for 4 weeks post treatment.Treatment-emergent adverse events (TEAEs) were higher with tapinarof(85/152 patients [56%] compared to vehicle 19/75 patients [25%]) andmild-to-moderate in intensity. Severe TEAEs were reported in alltapinarof groups except 0.5% QD. Study results showed a clear differencebetween the active treatment (Tapinarof cream) and the vehicle groupswith regards to the primary endpoint (proportion of subjects whoachieved a PGA score of 0 or 1 at Week 12 and a minimum 2-gradeimprovement in PGA score from Baseline to Week 12). Moreover, the 1%concentration groups showed a higher proportion of responder subjectsthan the 0.5% concentration groups at Week 12. Responses started at Week2 and increased in magnitude throughout the study with the 1%concentration groups, having a higher proportion of responders at eachtime point compared to the 0.5% concentration groups. PGA responsespersisted for 4 weeks after the end of treatment. Both applicationfrequencies (QD or BID) had a similar effect on the PGA response ratewithin each cream concentration.

In a very similar pattern to the PGA response rate, the main secondaryendpoint, the proportion of subjects with ≥75% improvement in PASI(PASI75) from Baseline to each study visit, was clearly higher in theactive treatment than in the vehicle groups. All tapinarof groups showeda clear separation from vehicle reaching statistical significance after8 weeks of treatment, with 1% concentration showing highest responserates (FIG. 9 ).

Similarly, the 1% concentration groups showed a higher proportion ofresponder subjects than the 0.5% concentration groups. Responses startedat Week 2 and increased in magnitude throughout the study with the 1%concentration groups, having a higher proportion of responders at eachtime point compared to the 0.5% concentration groups. PASI75 responseslasted at least 4 weeks after the end of treatment. Mean percent changereduction in PASI scores from Baseline to each study visit, as well asthe rate of PASI75 responders, was higher in the 1% concentration thanin the 0.5% concentration groups.

Nearly identical improvement over time was observed for the mean percentchange reduction in PASI scores for both 1% concentration groups (QD andBID), leading to the conclusion that the QD application had similarefficacy level to BID and would provide lower exposure than BID;therefore, it should be chosen for future Phase III studies. Also, theQD application offers an ease of use advantage that could lead to futuresubject treatment adherence.

The aforementioned efficacy results were unaltered when data wereanalyzed using a LOCF imputation method, confirming the robustness ofthe data.

Results from other clinical evaluations assessed from Baseline to eachstudy visit such as mean change reduction in percent of total BSAaffected, total target lesion grading scores (erythema, scaling andinduration/plaque thickness) and subject-reported outcomes (severity ofpsoriasis daily symptoms) as assessed by subject responses recorded in adaily symptom diary, were also supportive of the therapeutic effect ofTapinarof cream, as compared to vehicle. However, the secondary endpointof itch/pruritus severity did not follow this pattern; despite mostsubjects experiencing a decrease in itch/pruritus symptoms over thestudy period, no clear differences were observed between the activetreatment groups and the vehicle groups in the reduction of the symptomof itch/pruritus.

Subject's impressions of the severity of their psoriasis symptoms fromBaseline to Week 12, as well as investigators' assessments, correspondedwith the clinical evaluations.

Most subjects rated the change in the severity of their psoriasissymptoms, as well as the change in the severity of their itch symptoms,as “very improved” or “moderately improved” by the end of 12 weeks oftreatment with Tapinarof cream. Mean change reduction in weekly averagePSD symptom scores was higher in the active treatment groups than in thevehicle groups. Further, when data from 9 items with high severityscores at baseline were analyzed, weekly average change scores improvedmore for active treatment groups when compared to the vehicle groups atWeek 12.

Primary and main secondary endpoint analyses for the Japanese sub-groupwere consistent with the Overall Population.

Safety Discussion: The frequency of TEAEs was higher in the activetreatment groups than in the vehicle groups (56% and 25%, respectively)and more TEAEs were considered treatment-related in the active treatmentgroups (22%) than in the vehicle groups (3%). Most TEAEs were mild ormoderate, with 7% and 3% (in the active treatment and the vehiclegroups, respectively) being reported as severe. No deaths, no othersignificant AEs and no clinically-significant changes in laboratoryevaluations were reported during the study. The 1% QD treatment may havea slightly better safety profile than the 1% BID treatment, based on alower frequency of TEAEs.

The most commonly reported TEAE (regardless of relationship to studytreatment) was folliculitis (9%), which was also the most frequenttreatment-related TEAE (7%) (10% and 1% in the active treatment and thevehicle groups, respectively). Other treatment-related TEAEs were:contact dermatitis (3%) (all in the active treatment group) andapplication site dermatitis, application site irritation, allergicdermatitis, monocyte count decreased and headache (1% each)(all in theactive treatment groups except for 1 case of monocyte count decreased).The application site AEs occurred more frequently in the activetreatment groups compared with the vehicle groups. The contactdermatitis may have been provoked by the topical treatment beingdirectly applied on the skin; the application site dermatitis and theallergic dermatitis may have been related to the contact dermatitis.Headache was the fourth most frequent TEAE observed in this study, hasalready been reported in a Tapinarof Phase I study, and may showdose-response.

None of the serious TEAEs were treatment-related.

The tolerability of Tapinarof cream was very similar acrossconcentration groups (0.5% and 1%) and with both frequencies ofapplication (QD or BID). Tolerability improved from Week 1 to Week 12.

Safety: Overall, 46% (104/227) of subjects had treatment-emergent AEs(TEAEs): 56% in the tapinarof cream groups and 25% in the vehicle groups(Table 9), and were mostly mild to moderate in severity. The mostfrequently reported TEAE was folliculitis, which occurred in 20 (9%)subjects (13% in the tapinarof cream groups and 1% in the vehiclegroups).

TABLE 9 Safety overview and most common TEAEs occurring in >5% ofsubjects in any group Tapinarof 1% Tapinarof 0.5% Vehicle Preferredterm, BID QD BID QD BID QD n (%) (n = 40) (n = 41) (n = 43) (n = 41) (n= 42) (n = 40) Any TEAE 26 (68) 20 (53) 22 (58) 17 (45)  9 (24) 10 (26)Treatment- 10 (26) 10 (26)  6 (16)  8 (21) 1 (3) 1 (3) related TEAEsSerious TEAEs 1 (3) 3 (8) 3 (8) 0   0   0   Discontinuous  5 (13)  5(13)  4 (11) 1 (3) 0   1 (3) due to TEAEs TEAEs occurring in >5% ofsubjects in any group Folliculitis  8 (21) 2 (5)  4 (11)  5 (13) 1 (3)0   Dermatitis  4 (11)  4 (11) 1 (3) 3 (8) 0   0   contact Headache  4(11) 1 (3) 0   1 (3) 1 (3) 1 (3) Nasopharyngitis 1 (3) 0    4 (11) 2 (5)0   2 (5) Vomiting 0   0   3 (8) 0   1 (3) 0   Acne 2 (5) 0   1 (3) 0  0   0   Application-site  1 (3)* 2 (5) 0   1 (3) 0   0   dermatitisMiliaria 0   2 (5) 0   1 (3) 0   0   Dermatitis 2 (5) 0   0   0   0  0   allergic Urticaria 0   2 (5) 0   0   0   0   TEAE is defined as anAE which occurred on or after study treatment start date and on orbefore the last visit. *All TEAEs occurred once in each subject except‘application site dermatitis’, which occurred twice in a subject fromthe 1% BID group. BID, twice daily; QD, once daily; TEAE,treatment-emergent adverse event.

Overall, Tapinarof cream showed an acceptable safety and tolerabilityprofile.

Conclusions

The proportion of subjects who achieved a PGA score of clear or almostclear (0 or 1) at Week 12 and a minimum 2-grade improvement in PGA scorefrom Baseline to Week 12 was clearly higher in the active treatmentgroups than in the vehicle groups and was dose-dependent.

PGA responses were observed from Week 2, peaked at around Week 12 andwere durable, lasting up to 4 weeks after the end of treatment.

The effects of Tapinarof cream on the PGA response rate after QD and BIDapplications were similar.

The proportion of subjects with ≥75% improvement in PASI from Baselineto each study visit, was clearly higher in the active treatment groupsthan in the vehicle groups and was also dose-dependent.

PASI75 responses were observed from Week 2, peaked at around Week 12 andwere durable, lasting up to 4 weeks after the end of treatment.

Mean percent change reduction in PASI scores from Baseline to each studyvisit, as well as the rate of early PASI75 responders, were higher inthe 1% concentration group.

The effects of Tapinarof cream on the mean percent change reduction inPASI scores after QD and BID applications were similar, indicating thatthe QD application has similar efficacy level to BID and would providelower exposure than BID; therefore, it should be chosen for future PhaseIII studies. Also, the QD application offers an ease of use advantagethat could lead to future subject treatment adherence.

Evaluation of mean change reduction in percent of total BSA affected,total target lesion grading scores (erythema, scaling andinduration/plaque thickness), and subject-reported outcomes (severity ofpsoriasis daily symptoms) as assessed by subject responses recorded in apersonal symptom diary, were all supportive of the therapeutic effect ofTapinarof cream, as compared to vehicle.

Subject, as well as investigator impressions of the severity ofpsoriasis symptoms corresponded with clinical evaluations. Most subjectsrated the change in the severity of their psoriasis symptoms as “veryimproved” or “moderately improved” by the end of treatment withTapinarof cream (Week 12).

Tapinarof cream showed an acceptable safety profile. There were notreatment-related serious TEAEs reported. The most frequenttreatment-related TEAE was folliculitis, followed by contact dermatitis,application site dermatitis and application site irritation, allergicdermatitis, monocyte count decreased and headache.

No clinically-significant changes in laboratory evaluations werereported during the study.

The tolerability of Tapinarof cream was similar across concentrationgroups (0.5% and 1%) and with both frequencies of application (QD orBID). Tolerability improved from Week 1 to Week 12. The 1% QD treatmentmay have a slightly better safety profile than the 1% BID treatment.

Additional Analysis

Primary endpoint—efficacy based on percentage of patients who achievedminimum two-point improvement in PGA score and assessment of “clear” or“almost clear” skin, referred to as “treatment success.”

Secondary endpoint—PASI score, BSA score, change in target lesiongrading scores, psoriasis symptom diary scores, subject impressions ofsymptom severity and safety and tolerability.

At week 12, 65% of patients treated with 1% BID and 56% treated with 1%QD met treatment success, compared with 11% and 5% for vehicle BID andQD, respectively. At week 12, 46% of patients treated with 0.5% BID and36% treated with 0.5% QD met treatment success.

At week 12, 65% and 56% of patients achieved a 75% improvement in PASIscore in 1% BID and 1% QD groups, respectively, compared to 16% and 5%for BID and QD vehicle, respectively. The endpoint was met; statisticalsignificance was achieved for all tapinarof arms compared to vehicle(p<0.001).

At week 12, subjects treated with both 0.5% and 1% concentrations showedgreater improvement in mean change in percentage BSA affected frombaseline (as demonstrated by an absolute mean change in percent BSAaffected of 4.9 for 1% BID and 4.3 for 1% QD, respectively, comparedwith 1.6 for BID vehicle and 1.0 for QD vehicle). While statisticalsignificance was not evaluated for this endpoint, the endpoint wasdetermined to be met.

At week 12, subjects treated with both 0.5% and 1% concentrations showedgreater improvement in mean change in total target lesion grading scores(decreases of 6.9 for 1% BID and 7.0 for 1% QD, compared with 2.5 forBID vehicle and 2.1 for QD vehicle). The maximum total target lesiongrading score is 12 with a higher score indicating increased severity.The endpoint was met; statistical significance was achieved for alltapinarof arms compared to vehicle (p<0.001).

For psoriasis symptom diary scores, overall mean change reduction in theweekly average scores was generally higher in the treatment groups thanin vehicle groups. While statistical significance was not evaluated forthis endpoint, the endpoint was determined to be met.

At week 12, based on subject impressions of change in pruritus symptoms,most patients treated with tapinarof 1% (70% BID and 76% QD) andtapinarof 0.5% (77% BID and 72% QD) rated their itch to be “moderatelyimproved” to “very improved” compared to patients treated with vehicle(47% BID and 35% QD). Statistical significance was achieved, and theendpoint was met, for all tapinarof arms compared to vehicle (p<0.05),with the exception of 1% BID.

At week 12, based on subject impression of symptom severity, mostsubjects in the treatment groups (over 80% in the 1% groups and between77% and 79% in the 0.5% groups) rated the severity of their overallsymptoms, including reduction in severity of itch, as “very improved” or“moderately improved.” The endpoint was met; statistical significancewas achieved for all tapinarof arms compared to vehicle (p<0.05).

There was no significant percentage change versus vehicle at week 12 formean change in reduction in itch from baseline based on patients whoachieved a minimum four-point improvement in the itch NRS. Overall, mostpatients had a minimum four point improvement in itch over the studyperiod. As a result, we could not determine that this endpoint was met.

Generally well tolerated at 0.5% and 1% concentrations, with majority ofAEs and TAEs reported as mild or moderate. 109 subjects experiences atleast one AE (89 in treatment groups). 104 subjects experienced at leastone TEAE (85 in treatment groups). 36 subjects experience TEAEs thatwere considered related to treatment (34 subjects in treatment groups).The most common treatment-related TEAs were folliculitis, contactdermatitis and headache. Seven subjects reported SAEs, none of whichconsidered related to treatment. 16 subjects discontinued prior to endof treatment period.

Secondary Efficacy Outcomes from the Phase 2b, Randomized Dose-FindingStudy of Tapinarof Cream for the Treatment of Plaque Psoriasis

Study: This phase 2b, double-blind, six-arm, vehicle-controlledrandomized study (NCT02564042) assessed the efficacy and safety oftapinarof cream in subjects with psoriasis. Subjects (aged 18-65 years)with chronic stable plaque psoriasis (≥6 months), BSA involvement ≥1 and≤15% and Physician Global Assessment (PGA) score ≥2 at baseline wererandomized 1:1:1:1:1:1 to tapinarof cream 0.5% or 1.0% once (QD) ortwice daily (BID) or vehicle QD or BID for 12 weeks. Secondary efficacyoutcomes reported here include mean change from baseline in PGA, 50%reduction in Psoriasis Area and Severity Index (PASI50), PASI90, targetlesion grading scores, and pruritus numeric rating scale (NRS).

Results: Of 227 subjects randomized, 174 completed the study. HigherPASI50 and PASI90 response rates, and greater reductions in mean PGA andtotal target lesion grading scores were observed in tapinarof groups vsvehicle at Week 12; results were maintained for 4 weeks after the end ofstudy treatment (Table 10). Most treatment-emergent adverse events weremild or moderate, and the most common (≥50%) across all groups werefolliculitis (9%) and contact dermatitis (50%). Most incidences offolliculitis and contact dermatitis were mild or moderate.

Conclusion: These results support the primary analysis showing thattapinarof cream was efficacious and well tolerated in adults withpsoriasis.)¹ A phase 3 program is planned to further investigatetapinarof cream (1% QD) as a new treatment option for psoriasis.

TABLE 10 Secondary efficacy results at Week 12 Tapinarof 1% Tapinarof0.5% cream cream Vehicle Mean change in PGA scores BID QD BID QD BID QD(SD) from baseline at Week 12 (n = 23) (n = 25) (n = 26) (n = 28) (n =19) (n = 20) −1.8* −1.7* −1.7* −1.3* −0.5 −0.4 (0.9) (1.0) (1.1) (0.8)(0.8) (0.7) Mean change in total target BID QD BID QD BID QD lesiongrading scores (SD) (n = 23) (n = 25) (n = 26) (n = 29) (n = 19) (n =20) from baseline at Week 12 −6.9* −7.0* −6.2* −5.8* −2.5 −2.1 (2.9)(3.1) (3.0) (3.0) (2.8) (2.2) PASI50 response rates at BID QD BID QD BIDQD Week 12 (n = 23) (n = 25) (n = 26) (n = 28) (n = 19) (n = 20)  83%* 92%*  85%*  71%* 32% 10% PASI75 response rates at BID QD BID QD BID QDWeek 12 (n = 23) (n = 25) (n = 26) (n = 28) (n = 19) (n = 20)  65%^(†) 56%*  46%^(‡)  46%^(†) 16%  5% PASI90 response rates at BID QD BID QDBID QD Week 12 (n = 23) (n = 25) (n = 26) (n = 28) (n = 19) (n = 20) 39%^(†)  40%^(†)  31%^(†) 18% 0 0 Proportion of subjects who BID QD BIDQD BID QD achieved ≥ 4 improvement in (n = 11) (n = 11) (n = 18) (n =14) (n = 10) (n = 12) pruritus NRS score from 55% 73% 56% 57% 60% 33%baseline at Week 12 for subjects with baseline NRS score ≥4 *P < 0.001vs Vehicle. ^(†)P < 0.01 vs Vehicle. ^(‡)P < 0.05 vs Vehicle.

Patient-Reported Outcomes in Subjects with Plaque Psoriasis Treated withTapinarof Cream: Results from a Phase 2b, Randomized Parallel-GroupStudy

Study: This phase 2b, double-blind, six-arm, vehicle-controlled,randomized study (NCT02564042) assessed the efficacy and safety oftapinarof cream in subjects with psoriasis. Subjects (aged 18-65 years)with chronic stable plaque psoriasis (≥6 months), BSA involvement ≥1 and≤15% and Physician Global Assessment score ≥2 at baseline wererandomized 1:1:1:1:1:1 to tapinarof cream 0.5% or 1.0% once (QD) ortwice daily (BID) or vehicle QD or BID for 12 weeks. The primaryendpoint data was previously reported.¹ Patient-reported outcomesreported here include change in Psoriasis Symptom Diary (PSD) scores andsubject global impression of overall severity of psoriasis symptoms andoverall severity of pruritus from baseline to Week 12.

Results: Of 227 subjects randomized, 174 completed the study. Overall,43-61% of subjects rated their baseline symptoms as moderate; 28-44% assevere; and 3-13% as very severe. At week 12, a greater proportion ofsubjects in the tapinarof groups rated the overall severity of theirpsoriasis symptoms and pruritus symptoms as ‘very/moderately improved’compared with subjects in the vehicle groups (Table 11). Mosttreatment-emergent adverse events were mild or moderate, and the mostcommon (≥5%) across all groups were folliculitis (9%) and contactdermatitis (5%). Most incidences of folliculitis and contact dermatitiswere mild or moderate.

Conclusion: Subjects treated with tapinarof cream reported improvementsin symptoms, including pruritus from psoriasis, after 12 weeks vsvehicle. Overall, tapinarof cream was well tolerated.

TABLE 11 Patient-reported outcomes results at Week 12 Tapinarof 1%Tapinarof 0.5% cream cream Vehicle Proportion of subjects with severityBID QD BID QD BID QD of psoriasis symptoms rated as (n = 23) (n = 25) (n= 26) (n = 29) (n = 19) (n = 20) ‘very/moderately improved’ from 83%^(‡) 88%* 77%^(‡) 79%^(†) 47% 35% baseline to Week 12 Proportion ofsubjects with severity BID QD BID QD BID QD of pruritus symptoms ratedas (n = 23) (n = 25) (n = 26) (n = 29) (n = 19) (n = 20)‘very/moderately improved’ from 70% 76%^(†) 77%^(‡) 72%^(‡) 47% 35%baseline to Week 12 Mean change in nine items of the BID QD BID QD BIDQD PSD from baseline at Week 12 (n = 14) (n = 20) (n = 21) (n = 24) (n =15) (n = 18) [range 1 (very improved) to 7 (very −4.5^(‡) −4.0^(†)−4.2^(‡) −4.1^(†) −2.6 −1.9 worse)] *P < 0.001 vs Vehicle. ^(†)P < 0.01vs Vehicle. ^(‡)P < 0.05 vs Vehicle.

Example 3—Phase 2b, Randomized Clinical Trial of Tapinarof Cream for theTreatment of Plaque Psoriasis: Secondary Efficacy and Patient-ReportedOutcomes

Introduction

Psoriasis is a chronic, immune-mediated disease that is characterized byscaly, erythematous and pruritic plaques that can be painful anddisfiguring. The burden of psoriasis is similar to that of otherlong-term conditions, such as congestive cardiac failure and chroniclung disease, and has a profound impact on mental health and well-being.

Up to 71% of patients with psoriasis report a ‘moderate-to-extremelyhigh impact’ on their daily life. People with psoriasis experience ahigh treatment burden, with 88% reporting use of prescription topicalmedications and 83% reporting concomitant use of prescription andover-the-counter therapies. Patient satisfaction and preferences areclosely related to treatment compliance. For topical treatments, thevehicle can have a significant impact on adherence and long-termeffectiveness, with patients preferring creams to ointments, as creamsare considered less sticky and easier to apply.

Topical agents used as first-line therapy for psoriasis include vitaminD derivatives, corticosteroids, vitamin A derivatives (tazarotene), andanthralin. There are well-documented concerns and limitations withcurrent topical treatments, for example the vitamin D derivative,calcipotriene cream (0.005%) has been associated with skin irritationand elevated serum calcium levels; the topical retinoid, tazarotenecream (0.05% and 0.10%), has adverse events (AEs) that include pruritus,erythema, and burning; and mid-to-high-potency topical steroids havelimitations on duration and location of use due to concerns about localand systemic side effects. There is a clear need, therefore, foreffective topical therapies that can be used without body surface area(BSA) restrictions or duration of treatment limitations.

Tapinarof cream is a first-in-class therapeutic aryl hydrocarbonreceptor (AhR) modulating agent (TAMA) that is under investigation forthe treatment of psoriasis and atopic dermatitis. The efficacy oftapinarof in psoriasis is attributed to AhR-modulated downregulation ofinterleukin-17, skin barrier function enhancement, and antioxidantproperties via activation of the Nrf2 antioxidant pathway, a majorregulator of cytoprotective responses.

In the primary analysis of a phase 2b study in adults with psoriasis,tapinarof cream was efficacious and well-tolerated. Here we reportadditional efficacy and patient-reported outcomes (PROs) to furtherexplore the efficacy and tolerability of tapinarof cream in subjectswith psoriasis.

Methods

Study design: In this multicenter (United States, Canada, and Japan),phase 2b, double-blind, vehicle-controlled study, adult subjects withpsoriasis were randomized 1:1:1:1:1:1 to receive tapinarof cream 0.5% or1% once (QD) or twice daily (BID) or vehicle QD or BID for 12 weeks andfollowed up for 4 weeks after the end of study treatment. Detailed studydesign and primary endpoints were reported above. The study consisted of3 periods: up to 4 weeks' screening, 12 weeks' double-blind treatment,and 4 weeks' treatment-free follow-up. Study visits occurred atscreening; baseline; Weeks 1, 2, 4, 8, and 12 during the treatmentperiod; and 2 and 4 weeks after the last application of study treatment.

The study was conducted in compliance with the guidelines for GoodClinical Practice and the Declaration of Helsinki. Approval was obtainedfrom the local ethics committee or institutional review board at eachstudy center. All subjects provided written informed consent.

Subjects: Subjects were male or female adults aged 18-65 years, with aclinical diagnosis of chronic stable plaque psoriasis for ≥6 months, BSAinvolvement ≥1% to ≤15% (excluding scalp) at screening and baseline,Physician Global Assessment (PGA) score ≥2 at baseline, and 1 targetplaque located on the trunk or proximal parts of the extremities(excluding knees, elbows, and intertriginous areas) that measured ≥3 cm²at screening and baseline with severity representative of the subject'soverall disease. Key exclusion criteria were lesion infections and ahistory of, or ongoing, serious illness. Use of medications ortreatments that would significantly influence or exaggerate responses tothe study treatment were prohibited, including biologic agents,retinoids, immunomodulators, corticosteroids, and coal tar.

Study treatment: Subjects were instructed to apply a thin layer oftapinarof cream or vehicle to all psoriasis lesions (excluding scalp) QDor BID (at approximately the same time daily or 12 hours apart).Subjects were to continue to treat all original areas of involvement,even in the event of clearing of lesions, and were to apply cream to anynew lesions.

Outcome measures and statistical analysis: The previously reportedprimary efficacy endpoint was the proportion of subjects with a PGAscore of clear or almost clear (0 or 1) and ≥2-grade improvement in PGAscore from baseline to Week 12. Additional efficacy outcomes includedPGA scores, mean change in PGA and total target lesion grading scores,and ≥50%, ≥75%, and ≥90% improvement in Psoriasis Area and SeverityIndex (PASI50, PASI75, and PASI90) from baseline to each study visit.

PROs included change over time in daily Psoriasis Symptom Diary (PSD)scores and subject global impression of change in overall severity ofpsoriasis symptoms and pruritus symptoms from baseline to Week 12. ThePSD is a disease-specific, psychometrically validated, daily self-reporttool for the symptoms and functional impact of psoriasis. The PSD usedincluded the 16 questions in the established version, plus 6 additionalquestions to assess the severity and bother of skin flaking, dryness,and bleeding. Each PSD item is rated using an 11-point Numeric RatingScale, from 0 (absent) to 10 (worst imaginable). Subject globalimpression of change in overall severity of psoriasis symptoms andoverall severity of pruritus symptoms from baseline to Week 12 were alsoassessed. Subjects were asked to rate the overall severity of theirpsoriasis symptoms and pruritus symptoms at baseline on a scale of 1(mild) to 4 (very severe), and the change in overall severity ofpsoriasis symptoms and pruritus symptoms from baseline to Week 12 from 1(very improved) to 7 (very worse).

Safety assessments included incidence, frequency and severity of AEs,evaluation of local (application-site) tolerability, clinical laboratoryparameters, vital signs, electrocardiogram changes, and physicalexaminations. An unblinded Independent Data Monitoring Committeemonitored patient safety. Investigators assessed the overall degree ofirritation at the application sites using a scale of 0 (no irritation)to 4 (very severe/strong reaction) at each study visit. A score of 3 or4 was reported as an AE. Study treatment was discontinued if a score of4 was noted. Subject-reported tolerability was assessed using a 5-pointtolerability scale of 0 (none) to 4 (strong/severe) to assess thepresence and degree of burning/stinging and itching at the applicationsite within 2 hours following application of tapinarof or vehicle.

Efficacy analyses were conducted on observed cases in the modifiedintention-to-treat (mITT) population, which included all randomizedsubjects minus the subjects from one site, due to a protocol violation.Summary statistics of the number of subjects providing data at therelevant time point, frequency counts and percentages, and 95% exactconfidence interval were provided for each treatment group at each studyvisit.

Differences between arms were considered statistically significant at anα=0.05 level, where 95% confidence intervals excluded 0. P values fordifferences between tapinarof cream groups and corresponding vehiclegroups for PASI response rates at Weeks 12 and 16 were calculated posthoc using Barnard's and Fisher's exact tests. P values for PGA scoresand total target lesion grading scores at Weeks 12 and 16 were based ona post-hoc analysis of covariance with main effect of treatment andcovariates of average baseline selected score and pooled country.

Results

Subject disposition: Of the 290 subjects screened, 227 were randomized,196 were included in the mITT population, and 175 (77%) completed the12-week treatment phase. Overall, mean demographic and baselinecharacteristics were comparable across treatment groups (Table 12). Mostsubjects (80%) had a baseline PGA category of 3 (moderate). Baselinemean PASI score was 8.8 (standard deviation, 4.5).

TABLE 12 Baseline subject demographics and characteristics Tapinarof 1%Tapinarof 0.5% cream cream Vehicle BID QD BID QD BID QD (n = 38) (n =38) (n = 38) (n = 38) (n = 37) (n = 38) Age, mean 45.9 (11.9) 48.5(10.6) 49.6 (10.9) 48.7 (9.7) 46.7 (12.6) 46.4 (10.2) (SD), years Malesex, n 26 (68) 26 (68) 24 (63) 25 (66) 23 (62) 29 (76) (%) Weight, 85.6(22.5) 86.7 (22.6) 88.6 (27.4) 89.3 (23.1) 87.8 (28.3) 91.6 (21.6) mean(SD), kg PGA score, 2.9 (0.4) 2.7 (0.5) 3.0 (0.5) 2.9 (0.4) 3.0 (0.3)2.8 (0.4) mean (SD*) PASI score, 10.6 (5.0)  8.5 (3.6) 8.2 (4.5) 7.9(4.8) 9.0 (4.3) 8.7 (4.4) mean (SD)* BSA 8.2 (4.5) 6.5 (3.3) 7.2 (4.5)6.1 (4.3) 6.6 (3.6) 7.0 (4.6) affected, mean (SD), %* Pruritus 5.6 (2.6)4.4 (2.9) 6.2 (2.2) 4.5 (2.6) 5.5 (2.8) 4.9 (2.4) score, mean (SD)*^(†)

Primary efficacy endpoint: As previously reported, PGA response rate atWeek 12 was significantly higher in all tapinarof cream groups comparedwith vehicle groups (65% [1% BID]; 56% [1% QD]; 46% [0.5% BID]; 36%[0.5% QD] vs 11% [vehicle BID] and 5% [vehicle QD]) and was maintainedfor 4 weeks after the end of treatment through Week 16 in all activetreatment groups except for the 0.5% BID group. PGA response rates weresignificantly higher in all tapinarof groups compared with vehiclegroups from Week 8 onwards.

PGA scores: Mean improvements in PGA scores (SD) from baseline at Week12 were significantly higher in all tapinarof groups compared withvehicle groups (all P<0.001): −1.8 (0.9) 1% BID, −1.7 (1.0) 1% QD, −1.7(1.1) 0.5% BID, and −1.3 (0.8) 0.5% QD versus −0.5 (0.8) vehicle BID and−0.4 (0.7) vehicle QD.

PASI50, PASI75, and PASI90: PASI50 and PASI75 response rates weresignificantly higher in all tapinarof groups compared with vehiclegroups from Week 8 onwards. PASI50 response rates at Week 12 were 83%(1% BID), 92% (1% QD), 85% (0.5% BID), and 71% (0.5% QD) versus 32%(vehicle BID) and 10% (vehicle QD) (all P<0.001). Significant PASI50responses with tapinarof were maintained after the end of treatmentthrough Week 16: 83% (P<0.001; 1% BID), 77% (P<0.001; 1% QD), 62%(P=0.023; 0.5% BID), and 71% (P<0.001; 0.5% QD) versus 26% (vehicle BID)and 16% (vehicle QD).

PASI75 response rates at Week 12 were 65% (P=0.001; 1% BID), 56%(P<0.001; 1% QD), 46% (P=0.035; 0.5% BID), and 46% (P=0.002; 0.5% QD)versus 16% (vehicle BID) and 5% (vehicle QD). Significant PASI75responses with tapinarof were maintained after the end of treatmentthrough Week 16: 63% (P<0.001; 1% BID), 58% (P<0.001; 1% QD), 46%(P=0.012; 0.5% BID), and 54% (P<0.001; 0.5% QD) versus 11% (vehicle BID)and 5% (vehicle QD) (FIG. 10 ).

PASI90 responses rates were significantly higher in all tapinarofgroups, except the 0.5% QD group, compared with vehicle at Week 12: 39%(P=0.002; 1% BID), 40% (P=0.001; 1% QD), 31% (P=0.008; 0.5% BID), and18% (P=0.057; 0.5% QD); 0% (vehicle BID); and 0% (vehicle QD).Significantly higher PASI90 responses in the tapinarof groups weremaintained after the end of treatment through Week 16: 38% (P=0.002; 1%BID), 42% (P=0.001; 1% QD), 27% (P=0.014; 0.5% BID), and 18% (P=0.057;0.5% QD) versus 0% (vehicle BID) and 0% (vehicle QD) (FIG. 11 ).

PASI50/75/90 responses with tapinarof generally showed a separationversus vehicle starting at Week 2, with significantly superior efficacymaintained to Week 12 and after the end of treatment, through Week 16.

Total target lesion grading: Greater reductions in total target lesiongrading scores from baseline were observed in all tapinarof groupscompared with vehicle groups from Week 2 onwards, with significantlygreater reductions observed at Week 12 (all comparisons P<0.001).Significant improvements in total target lesion grading scores withtapinarof versus vehicle were maintained after the end of studytreatment through Week 16 (FIG. 12 ). The target lesion response of arepresentative subject randomized to tapinarof 1% QD at baseline, Week8, and Week 12 is shown in FIG. 13 .

Patient-reported outcomes: At baseline, 95% of subjects rated theirpsoriasis symptoms as moderate, severe, or very severe across alltreatment groups (3-13% rated as them as very severe, 28-44% rated themas severe, and 43-61% rated them as moderate). At Week 12, significantlymore subjects in the tapinarof groups rated the overall severity oftheir psoriasis symptoms as ‘very/moderately improved’ compared with thevehicle groups: 83% (P=0.019; 1% BID), 88% (P<0.001; 1% QD), 77%(P=0.045; 0.5% BID), and 79% (P=0.002; 0.5% QD) versus 47% (vehicle BID)and 35% (vehicle QD) (FIG. 14 ). Similarly, more subjects treated withtapinarof cream rated their pruritus symptoms at Week 12 as‘very/moderately improved’ compared with the vehicle groups: 70%(P=0.167; 1% BID), 76% (P=0.006; 1% QD), 77% (P=0.045; 0.5% BID), and72% (P=0.01; 0.5% QD) versus 47% (vehicle BID) and 35% (vehicle QD)(FIG. 15 ).

Overall, there was a greater reduction from baseline in mean weekly PSDscores in the tapinarof groups compared with the vehicle groups (FIG. 16). PSD items 2, 11, 12, 13, 14, 17, 18, 19, and 20 (related to itching,scaling, flaking, dryness, and appearance) showed high mean severityscores (≥5 overall) at baseline. By Week 12, scores from these items hadsignificantly reduced in tapinarof groups compared with vehicleindicating clinically meaningful symptom improvement.

Safety, tolerability, and treatment discontinuation: AEs were mostlymild to moderate in severity. The majority of subjects had little to noinvestigator-assessed treatment-site irritation or self-reportedapplication-site burning/stinging and itching throughout the studyperiod with no apparent differences between tapinarof and vehiclegroups. Investigator-reported tolerability scores were predominantly 0(‘no irritation’) at Week 1 and were maintained through Week 12 (FIG. 17). Subject-reported tolerability scores were predominantly 0 or 1(‘none’ or ‘slight’ application-site burning/stinging and itching) atWeek 1 and improved in all groups over the treatment period through Week12 (FIG. 18 ).

Discussion

These results support the previously reported primary analysis showingthat tapinarof cream was efficacious and well-tolerated in adults withpsoriasis. Tapinarof cream was significantly more efficacious thanvehicle in improving PGA response rates at Week 12, which weremaintained for 4 weeks during the treatment-free follow-up (Week 16).

Treatment with tapinarof cream resulted in improvements in PASI50 andPASI75 from Week 2, which were statistically significant at Week 8through Week 16. PASI90 response analyses followed a similar trend ofearly, durable, and statistically significant efficacy of tapinarof. Thesustained durability of response observed in the phase 2b study isintriguing and may provide additional benefit to patients, which will befurther explored in phase 3 studies.

The 1% tapinarof cream groups showed higher response rates than 0.5%groups, although response rates were similar in the tapinarof QD and BIDgroups, suggesting that optimal responses can be achieved with theconvenience and improved tolerability of QD dosing.

Total target lesion grading scores improved from Week 2 onwards withtapinarof cream compared with vehicle, and differences were maintainedduring the treatment-free follow-up (Week 16). By Week 12, asignificantly higher proportion of subjects treated with tapinarof 1% QDreported very or moderately improved psoriasis symptoms andpsoriasis-related pruritus compared with vehicle QD. These improvementsin patient reported outcomes indicate that tapinarof may have abeneficial effect on life quality, psychological well-being, andtreatment satisfaction.

The improvements obtained as early as Week 2 in the tapinarof cream 1%QD group, together with the maintenance of effect observed 4 weeks afterthe cessation of treatment, are promising and warrant furtherinvestigation, as early and significant clinical improvement, QD dosing,and maintenance of effect are important factors in ensuring patientadherence and overall treatment success.

Overall, tapinarof cream was well-tolerated, with most AEs reported asmild or moderate.

These results suggest that tapinarof cream is an important advance intopical therapy, having beneficial effects on a range of objective andPROs in psoriasis. The combination of tolerability, efficacy, anddurability of response observed suggests that tapinarof has thepotential to provide a novel and clinically effective therapeutic optionthat could help address known limitations of current topical medicinesavailable to this patient population. A phase 3 study of tapinarof cream1% QD in psoriasis is ongoing (NCT03956355).

Example 4—Tapinarof Cream for the Treatment of Plaque Psoriasis:Efficacy and Safety by Baseline Disease Characteristics and Skin Type ina Phase 2b Randomized Study

Tapinarof is a therapeutic aryl hydrocarbon receptor modulating agent(TAMA) in development for the treatment of psoriasis and atopicdermatitis. In a previously reported phase 2b efficacy and safety study(NCT02564042), Physician Global Assessment (PGA) responses (0 or 1 and≥2-grade improvement from baseline) at Week 12 were significantly higherin all tapinarof cream groups vs vehicle. Tapinarof cream demonstrateddurable PGA responses through 4 weeks after the end of study treatment.

A post-hoc analysis of PGA response stratified by baseline % bodysurface area (BSA) affected, psoriasis duration, and Fitzpatrick skintype was conducted to evaluate the efficacy and safety of tapinarofcream vs vehicle across subgroups.

Overall, mean baseline disease characteristics were comparable acrossgroups. Most subjects (80%) had a baseline PGA score of 3 (moderate).Mean baseline Psoriasis Area and Severity Index score was 8.8.

Stratified by baseline BSA, PGA response at Week 12 in subjects treatedwith tapinarof 1% twice daily (BID), 1% once daily (QD), 0.5% BID, and0.5% QD vs vehicle BID and vehicle QD was: 67%, 60%, 33%, and 35% vs 13%and 6%, respectively (1 to <10% BSA affected; n=102); and 64%, 40%, 75%,and 38% vs 0% and 0%, respectively (≥10% BSA affected; n=39).

Stratified by psoriasis duration, PGA response at Week 12 in subjectstreated with tapinarof 1% BID, 1% QD, 0.5% BID, and 0.5% QD vs vehicleBID and vehicle QD was: 50%, 80%, 50%, and 29% vs 0% and 0%,respectively (6 months to <5 years; n=27); 67%, 50%, 20%, and 50% vs 25%and 0% (5 years to <10 years; n=32); and 73%, 50%, 53%, and 33% vs 8%and 8% (≥10 years; n=82).

Stratified by Fitzpatrick skin type, PGA response at Week 12 in subjectstreated with tapinarof 1% BID, 1% QD, 0.5% BID, and 0.5% QD vs vehicleBID and vehicle QD was: 60%, 67%, 50%, and 25% vs 0% and 10%,respectively (Fitzpatrick skin type I/II; n=41); 54%, 47%, 60%, and 44%vs 18% and 0% (Fitzpatrick skin type III/IV; n=73); and 100%, 75%, 25%,and 25% vs 0% and 0% (Fitzpatrick skin type V/VI; n=27).

Incidence and type of adverse events were generally comparable acrossgroups and consistent with those observed in the overall population.

Tapinarof cream was efficacious and well tolerated across subgroupsregardless of baseline % BSA affected, psoriasis duration, orFitzpatrick skin type. A phase 3 study of tapinarof cream 1% QD inpsoriasis is ongoing (NCT03956355).

Study Design: In this multicenter (United States, Canada, and Japan),phase 2b, double-blind, vehicle-controlled randomized study, adultsubjects with psoriasis were randomized 1:1:1:1:1:1 to receive tapinarofcream 0.5% or 1% once (QD) or twice daily (BID) or vehicle QD or BID for12 weeks and followed up for 4 more weeks (FIG. 19 )

Study Outcomes and Statistical Analysis: The primary endpoint wasPhysician Global Assessment (PGA) response rates at Week 12, defined asthe proportion of subjects with a PGA score of clear or almost clear (0or 1) and ≥2-grade improvement in PGA score from baseline to Week 12.Additional post-hoc efficacy analyses reported here include PGA responserates at Week 12, stratified by the following baseline diseasecharacteristics and skin type: Baseline % BSA affected: 1 to ≤10% and≥10%, Baseline duration of psoriasis: 6 months to <5 years, 5 years to<10 years, and ≥10 years, Fitzpatrick skin type: Fitzpatrick skin type Iand II, Fitzpatrick skin type III and IV, and Fitzpatrick skin type Vand VI. Incidence, frequency, and nature of adverse events (AEs) andserious AEs were collected from the start of study treatment until theend of study visit at Week 16.

Results

Subject Characteristics: A total of 227 subjects (of the 290 subjectsoriginally screened) were randomized (intent-to-treat population) and ofthose randomized, 175 subjects (77%) completed the study, including theWeek 16 follow-up visit. Mean demographic and baseline characteristicswere comparable across treatment groups (Table 13). Overall, 15% ofsubjects had a baseline PGA category of 2 (mild), 80% had a PGA categoryof 3 (moderate), and 5% had a PGA category of 4 (severe). Baseline meanPsoriasis Area and Severity Index score was 8.8 (standard deviation [SD]4.5).

TABLE 13 Baseline Subject Demographics and Characteristics Tapinarof 1%Tapinarof 0.5% cream cream Vehicle BID QD BID QD BID QD (n = 38) (n =38) (n = 38) (n = 38) (n = 37) (n = 38) Age, mean 45.9 (11.9) 48.5(10.6) 49.6 (10.9) 48.7 (9.7)  46.7 (12.6) 46.4 (10.2) (SD), years Malesex, n 26 (68) 26 (68) 24 (63) 25 (66) 23 (62) 29 (76) (%) Weight, 85.6(22.5) 86.7 (22.6) 88.6 (27.4) 89.3 (23.1) 87.8 (28.3) 91.6 (21.6) mean(SD), kg PGA score, 2.9 (0.4) 2.7 (0.5) 3.0 (0.5) 2.9 (0.4) 3.0 (0.3)2.8 (0.4) mean (SD*) PASI score, 10.6 (5.0)  8.5 (3.6) 8.2 (4.5) 7.9(4.8) 9.0 (4.3) 8.7 (4.4) mean (SD)* BSA 8.2 (4.5) 6.5 (3.3) 7.2 (4.5)6.1 (4.3) 6.6 (3.6) 7.0 (4.6) affected, mean (SD), %* Pruritus 5.6 (2.6)4.4 (2.9) 6.2 (2.2) 4.5 (2.6) 5.5 (2.8) 4.9 (2.4) score, mean (SD)*^(†)Fitzpatrick 2 (6) 3 (9) 1 (3) 2 (6) 1 (3) 1 (3) skin type I, n (%)Fitzpatrick  8 (24)  7 (20)  10 (31)  6 (19)  5 (17) 13 (39) skin typeII, n (%) Fitzpatrick 17 (50) 14 (40)  6 (19) 13 (41) 11 (37) 11 (33)skin type III, n (%) Fitzpatrick 2 (6)  7 (20)  7 (22)  7 (22)  7 (23) 5 (15) skin type IV, n (%) Fitzpatrick  5 (15) 3 (9)  5 (16)  4 (13)  5(17) 3 (9) skin type V, n (%) Fitzpatrick 0   1(3) 3 (9) 0   1 (3) 0  skin type VI, n (%) Baseline disease characteristics provided for themITT population (n = 196), which included subjects in the ITT populationminus the subjects from one site due to protocol violation. Demographics(age, sex, and weight) provided for the safety population (n = 227).*Mean scores based on a scale of 0 ‘absent’ to 10 ‘worst imaginable’;data provided for subjects with available results (n = 32, 35, 30, 32,29, and 32, respectively). BID, twice daily; BSA, body surface area;ITT, intent-to-treat; mITT, modified intent-to-treat; PASI, PsoriasisArea and Severity Index; PGA, Physician Global Assessment; QD, oncedaily; SD, standard deviation.

PGA Response Rates: Primary endpoint: PGA response rates (defined as PGAscore 0 or 1 and ≥2-grade improvement) at Week 12 were significantlyhigher (at 0.05 significance level) in the tapinarof cream groups thanthe vehicle groups (65% [1% BID], 56% [1% QD], 46%[0.5% BID], 36% [0.5%QD] vs 11% [vehicle BID] and 5% [vehicle QD]) and were maintained for 4weeks after the end-of-study treatment in all active treatment groupsexcept for the 0.5% BID group.

PGA Response Rates by Baseline % BSA Affected: PGA response rates atWeek 12 were higher in tapinarof cream groups than vehicle groups,regardless of baseline % BSA affected (FIG. 20 ), 1 to <10% BSA affected(n=102): 67% (1% BID), 60% (1% QD), 33% (0.5% BID), and 35% (0.5% QD) vs13% (vehicle BID) and 6% (vehicle QD), ≥10% BSA affected (n=39): 64% (1%BID), 40% (1% QD), 75% (0.5% BID), and 38% (0.5% QD) vs 0% (vehicle BID)and 0% (vehicle QD).

PGA Response Rates by Baseline Duration of Psoriasis: PGA response ratesat Week 12 were higher in tapinarof cream groups than in vehicle groups,regardless of baseline duration of psoriasis, except for the 0.5% BIDtreatment group in the 5 years to <10 years subgroup (FIG. 21 ), 6months to <5 years (n=27): 50% (1% BID), 80% (1% QD), 50% (0.5% BID),and 29% (0.5% QD) vs 0% (vehicle BID) and 0% (vehicle QD); 5 years to<10 years (n=32): 67% (1% BID), 50% (1% QD), 20% (0.5% BID), and 50%(0.5% QD) vs 25% (vehicle BID) and 0% (vehicle QD); ≥10 years (n=82):73% (1% BID), 50% (1% QD), 53% (0.5% BID), and 33% (0.5% QD) vs 8%(vehicle BID) and 8% (vehicle QD).

Safety: Treatment-emergent AEs (TEAEs) were mostly mild to moderate inseverity. The most common treatment-related TEAEs were folliculitis (10%tapinarof vs 1% vehicle), contact dermatitis (3%; all tapinarof), andheadache (1%; all tapinarof). Incidence and type of AEs were generallycomparable across subgroups and consistent with those observed in theoverall population

Conclusions

Overall, tapinarof cream was efficacious and well tolerated regardlessof baseline % BSA affected, psoriasis duration, and Fitzpatrick skintype (FIG. 22 ). Higher PGA response rates at Week 12 were observed inthe 1% QD tapinarof cream group vs vehicle across all subgroups. Thesefindings support the previously reported efficacy and safety outcomes ofthe overall population. A phase 3 study of tapinarof cream 1% QD inpsoriasis is ongoing.

What is claimed:
 1. A method for treating mild to severe atopicdermatitis in a subject comprising topically administering a topicalcomposition containing about 1.0% tapinarof to affected areas of thesubject once a day, wherein after topically administering the topicalcomposition an Investigator Global Assessment (IGA) score is improved by2 grades.
 2. The method of claim 1, wherein the topical composition isan oil-in-water emulsion.
 3. The method of claim 2, wherein the oilphase of the oil-in-water emulsion is comprised of medium chaintriglycerides, propylene glycol, non-ionic emulsifying wax, diethyleneglycol monoethyl ether, polyoxyl stearyl ether-2, polysorbate 80,polyoxyl stearyl ether-20, benzoic acid, and butylated hydroxytolueneand the water phase of the oil-in-water emulsion is comprised of sodiumcitrate, edetate disodium, citric acid monohydrate, and water.
 4. Themethod of claim 1, wherein the topically administering includesapplication to the affected area of the skin selected from the groupconsisting of body, arms, legs, back, chest, buttocks, neck, scalp,fingernails, toenails, and combinations thereof.
 5. The method of claim1, further comprising, after topically administering the topicalcomposition, an improvement of one or more symptom of mild to severeatopic dermatitis as measured according to an assessment selected fromthe group consisting of Investigator Global Assessment (IGA) score,daily Itch/Pruritus numeric rating scale, Eczema Area and Severity Index(EASI), total severity score, percent body surface area (BSA) affected,sleep quality, dry/rough skin, red/discolored skin, flaky skin, visualanalogue scale (VAS) for sleep, and visual analogue scale (VAS) foritch.
 6. The method of claim 5, wherein the Itch/Pruritus numeric ratingscale is improved by 3 points.
 7. The method of claim 5, wherein theEczema Area and Severity Index (EASI) is improved by greater than orequal to 50% or is improved by greater than or equal to 75%.
 8. Themethod of claim 5, wherein the sleep quality is improved as measured bythe visual analogue scale (VAS) for sleep.
 9. The method of claim 5,wherein the one or more symptom is improved after about 2 weeks, about 4weeks, or about 8 weeks of administering the topical composition. 10.The method of claim 5, wherein the improvement of one or more symptomcontinues for about 4 weeks after administration of the topicalcomposition has ceased.
 11. The method of claim 1, wherein the IGA scoreis improved after about 2 weeks, about 4 weeks, or about 8 weeks ofadministering the topical composition.
 12. The method of claim 1,wherein the improvement in IGA score continues for about 4 weeks afteradministration of the topical composition has ceased.
 13. The method ofclaim 1, wherein the topically administering a topical compositioncontaining about 1.0% tapinarof results in systemic exposure oftapinarof that is below the limit of detection.
 14. The method of claim1, further comprising after topically administering the topicalcomposition an improvement of one or more symptom of mild to severeatopic dermatitis as measured according to an assessment selected fromthe group consisting of daily Itch/Pruritus numeric rating scale (NRS),total severity score (TSS), dry/rough skin, red/discolored skin, flakyskin, visual analogue scale (VAS) for sleep, visual analogue scale (VAS)for itch, and combinations thereof.
 15. The method of claim 1, whereinafter topically administering the topical composition an InvestigatorGlobal Assessment (IGA) score has improved to a score of 0 or
 1. 16. Amethod for treating mild to severe atopic dermatitis in a subjectcomprising topically administering a topical composition containingabout 1.0% tapinarof to affected areas of the subject once a day,wherein after topically administering the topical composition anInvestigator Global Assessment (IGA) score has improved to a score of 0or
 1. 17. The method of claim 16, wherein the topical composition is anoil-in-water emulsion.
 18. The method of claim 17, wherein the oil phaseof the oil-in-water emulsion is comprised of medium chain triglycerides,propylene glycol, non-ionic emulsifying wax, diethylene glycol monoethylether, polyoxyl stearyl ether-2, polysorbate 80, polyoxyl stearylether-20, benzoic acid, and butylated hydroxytoluene and wherein thewater phase of the oil-in-water emulsion is comprised of sodium citrate,edetate disodium, citric acid monohydrate, and water.
 19. The method ofclaim 16, wherein the topically administering includes application tothe affected area of the skin selected from the group consisting ofbody, arms, legs, back, chest, buttocks, neck, scalp, fingernails,toenails, and combinations thereof.
 20. The method of claim 16, furthercomprising, after topically administering the topical composition, animprovement of one or more symptom of mild to severe atopic dermatitisas measured according to an assessment selected from the groupconsisting of Investigator Global Assessment (IGA) score, dailyItch/Pruritus numeric rating scale, Eczema Area and Severity Index(EASI), total severity score, percent body surface area (BSA) affected,sleep quality, dry/rough skin, red/discolored skin, flaky skin, visualanalogue scale (VAS) for sleep, and visual analogue scale (VAS) foritch.
 21. The method of claim 20, wherein the Itch/Pruritus numericrating scale is improved by 3 points.
 22. The method of claim 20,wherein the Eczema Area and Severity Index (EASI) is improved by greaterthan or equal to 50% or is improved by greater than or equal to 75%. 23.The method of claim 20, wherein the sleep quality is improved asmeasured by the visual analogue scale (VAS) for sleep.
 24. The method ofclaim 20, wherein the one or more symptom is improved after about 2weeks, about 4 weeks, or about 8 weeks of administering the topicalcomposition.
 25. The method of claim 20, wherein the improvement of oneor more symptom continues for about 4 weeks after administration of thetopical composition has ceased.
 26. The method of claim 16, wherein theIGA score is improved after about 2 weeks, about 4 weeks, or about 8weeks of administering the topical composition.
 27. The method of claim16, wherein the improvement in IGA score continues for about 4 weeksafter administration of the topical composition has ceased.
 28. Themethod of claim 16, wherein the topically administering a topicalcomposition containing about 1.0% tapinarof results in systemic exposureof tapinarof that is below the limit of detection.
 29. The method ofclaim 16, further comprising after topically administering the topicalcomposition an improvement of one or more symptom of mild to severeatopic dermatitis as measured according to an assessment selected fromthe group consisting of daily Itch/Pruritus numeric rating scale (NRS),total severity score (TSS), dry/rough skin, red/discolored skin, flakyskin, visual analogue scale (VAS) for sleep, visual analogue scale (VAS)for itch, and combinations thereof.